Sofía Sánchez Iglesias
Mechanisms of aluminium neurotoxicity in oxidative stress-induced degenerative processes in relation to Parkinson's disease Tesis Doctoral
2009
Universidade de Santiago de Compostela Facultade de Medicina Departamento de Bioquímica e Bioloxía Molecular
Mechanisms of aluminium neurotoxicity in oxidative stress-induced degenerative processes in relation to Parkinson's disease
Tesis doctoral Sofía Sánchez Iglesias 2009
Universidade de Santiago de Compostela Facultade de Medicina Departamento de Bioquímica e Bioloxía Molecular
Mechanisms of aluminium neurotoxicity in oxidative stress-induced degenerative processes in relation to Parkinson’s disease
Estudio de los mecanismos de neurotoxicidad del aluminio en procesos degenerativos por estrés oxidativo relacionados con la enfermedad de Parkinson
MEMORIA presentada por SOFÍA SÁNCHEZ IGLESIAS para optar al Grado de Doctor en Bioquímica Santiago de Compostela 2009
Don Ramón Soto Otero y Doña Estefanía Méndez Álvarez, profesores titulares del Departamento de Bioquímica y Biología Molecular de la Universidad de Santiago de Compostela,
INFORMAN: Que la presente memoria titulada Estudio de los Mecanismos de Neurotoxicidad del Aluminio en Procesos Degenerativos por Estrés Oxidativo Relacionados con la Enfermedad de Parkinson, presentada por Doña Sofía Sánchez Iglesias para optar al grado de Doctor en Bioquímica, ha sido realizada bajo nuestra dirección en los Laboratorios del Departamento de Bioquímica y Biología Molecular de esta Universidad, y considerando que constituye trabajo de tesis y reúne los requisitos necesarios para ser valorado por el tribunal correspondiente, autorizamos su presentación al Consejo de Departamento correspondiente. Y para que así conste y surta los efectos oportunos, firmamos el presente informe en Santiago de Compostela a 15 de octubre de 2009.
El Director de la Tesis
La Directora de la Tesis
Ramón Soto Otero Profesor titular Dpto. Bioquímica y Biología Molecular
Estefanía Méndez Álvarez Profesora titular Dpto. Bioquímica y Biología Molecular
El Doctorando
Sofía Sánchez Iglesias
Esta Tesis Doctoral forma parte de los Proyectos de Investigación:
“Estudio de los mecanismos de neurotoxicidad del aluminio en procesos degenerativos por estrés oxidativo relacionados con la enfermedad de Parkinson” de la Xunta de Galicia (PGIDIT03PXIB20804PR; 2003-2006).
“Búsqueda de un nuevo fármaco para el tratamiento de la enfermedad de Parkinson con una doble acción farmacológica: inhibidora MAO-B y neuroprotectora frente al estrés oxidativo inducido por dopamina” del Ministerio de Ciencia y Tecnología con la contribución del Fondo Europeo de Desarrollo Regional (BFI2003-00493; 2004-2007).
“Búsqueda de un nuevo fármaco para el Parkinson: Inhibidor MAO-B y protector de los efectos inducidos por la dopamina sobre la cadena de transporte electrónico mitocondrial” del Ministerio de Ciencia e Innovación (SAF2007-66114; 2007-2010).
La realización de esta Tesis ha sido posible gracias a la concesión de las becas y ayudas de la Xunta de Galicia y de Roche Research Foundation (Suiza).
Acknowledgements
The work of this thesis could not have been accomplished if it wasn’t for the people below. First and foremost I wish to express my sincere gratitude and appreciation to my two excellent directors of the thesis, Prof. Ramón Soto-Otero and Prof. Estefanía Méndez-Álvarez. It has been an honour to work with you and learn from you. Thank you Ramón for given me the opportunity to work within the Neurochemistry research group and for providing me an exciting research project. Your insightful advice, guidance, and support make my Ph.D. experience productive and stimulating. Thank you Fanny for your continuous encouragements, patience, and valuables feedbacks. I wish to express special thanks to my colleague and friend Javier IglesiasGonzález who shared with me a lot of ideas and provided a dynamic and stimulating environment. Javi, thank you for your professional and personal support that made my graduate experience more enjoyable. I don’t forget our valuable discussions and our numerous memorable giggles; it has been a pleasure working together. I wish to express my appreciation to all members past or present of the Neurochemistry research group that I have had the pleasure to work with or alongside, especially Dr. Álvaro Hermida-Ameijeiras for his guidance and assistance in the first years of this work. Grateful acknowledgements are also made to Prof. José Luis Labandeira-García for constructive criticism and detailed review during the preparation of the publications, Prof. Jannette Rodriguez Pallares for excellent advice, Dr. Ana MuñozPatiño and Pablo Rey for immunohistochemistry studies, and Prof. Pilar BermejoBerrera and Prof. María del Carmen Barciela-Alonso for electrothermal atomic absorption spectrometry experiments.
Now life is not only science, I would therefore use this opportunity to thank my best friend Rosi for her patience and care during good and tough times in the Ph.D. pursuit. Always beside me. Finally, I would like to dedicate this work to my family: my grandmother Carmen and my grandfather Jesús always in my mind, my brother Jesús for his way of being, and very especially my parents María del Carmen and Alfonso for their unending love and support from ever. Thank you.
Abbreviations AA AD ADH BBB BG BHT BioH4 BSA CaM CAT CBD Cdk5 CMA CNS COMT COX-2 CSF CT CySH DA DAergic DAT DES DLB DMV DOPAC DOPAL eNOS EOPD ER FeBAD GABA GPCR GPe GPi GPx GR GSH
ascorbic acid Alzheimer’s disease aldehyde dehydrogenase blood-brain barrier basal ganglia butylated hydroxytoluene 5,6,7,8-tetrahydrobiopterin bovine serum albumine calmodulin catalase corticobasal degeneration cyclin-dependent kinase 5 chaperone mediated autophagy central nervous system catechol-O-methyl transferase cyclooxygenase-2 cerebrospinal fluid computarized tomography cysteine 3-hydroxytyramine hydrochloride (dopamine) dopaminergic dopamine transporter dialysis encephalopathy syndrome dementia with Lewy bodies dorsal motor nucleus of the vagus dihydroxyphenylacetic acid 3,4-dihydroxyphenylacetaldehyde endothelial nitric oxide synthase early onset of Parkinson’s disease endoplasmic reticulum fetal basis of adult disease -aminobutyric acid G-protein coupled receptor external globus pallidus internal globus pallidus glutathione peroxidase glutathione reductase reduced glutathione
Abbreviations (continuation) GSSH H2O2 HVA IL iNOS IP3 JP KO LB L-DOPA LN LPS Maneb MAO MAPK MDA MEF2 MFB mGLUR Mit MPP+ MPPP MPTP MRI MSA mtDNA MTP NBM NINDS NMDAR nNOS NO● / NO O2 O2●─ oatp ● OH 6-OHDA ONOO●─
oxidized glutathione hydrogen peroxide homovanillic acid interleukin inducible nitric oxide synthase inositol triphosphate juvenile parkinsonism knock-out Lewy body 3,4-dihydroxy-L-phenylalanine Lewy neurite lipopolysaccharide manganese ethylenebisadithiocarbamate monoamine oxidase mitogen-activated protein kinase malonodialdehyde myocyte enhancer factor 2 median forebrain bundle metabotropic glutamate receptor mitochondria 1-methyl-4-phenyl pyridinium ion 1-methyl-4-phenyl-4-propionoxy-piperidine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine magnetic resonance imaging multiple system atrophy mitochondrial DNA mitochondrial transition pore nucleus basalis of Meynert National Institute of Neurological Disorders and Stroke glutamate N-methyl-D-aspartate receptor neuronal nitric oxide synthase nitric oxide oxygen superoxide anion organic anion transporting polypeptide hydroxyl radical 6-hydroxydopamine peroxynitrite
Abbreviations (continuation) PCC PCD PD PET PI PIP2 PI-PLC PKC PQ Prx2 PSP PTC RNS ROOH ROS SN SNpc SNpr SOD SPECT STN t½ TBA TBARS TEP TH TH-ir TNF- TPN UPS VTA wt YOPD
protein carbonyl content programmed cell death Parkinson’s disease positron emission tomography phosphatidylinositol phosphatidylinositol biphosphate phosphatidylinositol-specific phospholipase C protein kinase C 1,1’-dimethyl-4,4’-bipyridinium, paraquat peroxiredoxin 2 progressive supranuclear palsy protein thiol content reactive nitrogen species hydroperoxides reactive oxygen species substantia nigra substantia nigra pars compacta substantia nigra pars reticularis superoxide dismutase single photon emission computarized tomography subthalamic nucleus half life thiobarbituric acid thiobarbituric acid reactive substances 1,1,3,3-tetraethoxypropane tyrosine hydroxylase, tyrosine 3-monooxygenase tyrosine hydroxylase immunoreactivity tumour necrosis factor- total parenteral nutrition ubiquitin-proteasome system ventral tegmental area wild type young-onset PD
List of figures Introduction Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 Figure 20 Figure 21 Figure 22 Figure 23
An essay of the shaking palsy The Parkinson’s complex Dopamine synthesis Dopamine catabolism Dopamine pathways Distribution of DA receptors in normal brain The basal ganglia Direct and indirect pathway in normal BG circuits SNpc depigmentation Human brain sections immunostained for DAT Basal ganglia: normal and parkinsonian state LB and LN in PD patients and localization of LB and LN Six stages Braak’s system Immunosections of stages 3-6 of Braak’s system MPTP metabolism The multiple hit model of PD Pathologic mechanisms in the etiology of PD The ubiquitin-proteasome system Generation of ROS and RNS in SNpc neuron Interaction between microglia and DAergic neurons Soluble aluminium ions as a function of solution pH Effects of aluminium and iron on the membrane peroxidation PIP2 hydrolisis altered by aluminium
1 3 12 13 14 14 15 16 17 18 19 22 24 24 28 31 32 34 43 47 54 68 69
Changes in TBARS levels in the ipsilateral and contralateral side of both striatum and ventral midbrain after stereotaxic, unilateral, intrastriatal injection of 6-OHDA to rats Changes in PCC in the ipsilateral and contralateral side of both striatum and ventral midbrain after stereotaxic, unilateral, intrastriatal injection of 6-OHDA to rats Changes in PTC in the ipsilateral and contralateral side of both striatum and ventral midbrain after stereotaxic, unilateral, intrastriatal injection of 6-OHDA to rats
97
Chapter 1 Figure 1
Figure 2
Figure 3
98
99
Chapter 2 Figure 1
Levels of aluminium in the different areas of the rat brain
113
List of figures (continuation) Chapter 3 Figure 1
Figure 2 Figure 3 Figure 4 Figure 5 Figure 6
Levels of TBARS, protein carbonyls, and protein thiols in different brain areas of rats i.p. treated with saline or aluminium chloride for ten days Enzyme activity of SOD, GPx, and CAT in different brain areas of rats i.p. treated with saline or aluminium chloride for ten days Microphotographs showing changes in the striatal TH-ir one week post-lesion in rats injected intraventricularly Density of striatal DAergic terminals estimated as optical density, one week post-surgery in the different experimental groups. Levels of TBARS, protein carbonyls, and protein thiols in both ventral midbrain and striatum of different groups of rats In vitro effects of aluminium on TBARS formation, protein carbonyl content, and protein thiol content induced by the autoxidation of 6-OHDA in mitochondrial preparations from rat brain
138-139
140-141 142 143 144-145 146-147
List of tables Introduction Table 1 Table 2 Table 3 Table 4 Table 5
Differential diagnostic in parkinsonian disorders UK Parkinson’s Disease Society Brain Bank’s diagnostic criteria for the diagnosis of probable PD National Institute of Neurological Disorders (NINDS) diagnostic criteria for PD Gene loci associated with PD Lipid composition of normal adult human brain
9 10
Graphite furnace programme for aluminium determination by ETAAS
113
In vitro effects of the presence of aluminium on the enzyme activities of SOD, GPx, CAT, and MAO
137
11 26 65
Chapter 2 Table 1
Chapter 3 Table 1
TABLE OF CONTENTS INTRODUCTION ....................................................................................... 1 PARKINSON’S DISEASE ...................................................................................................... 1 An overview ............................................................................................................................................ 1 Prevalence and incidence of PD .............................................................................................................. 2 Clinical characteristics of PD ................................................................................................................... 3 Resting tremor ....................................................................................................................................................................... 4 Rigidity ................................................................................................................................................................................... 4 Bradykinesia ........................................................................................................................................................................... 5 Postural instability ................................................................................................................................................................. 5 Progression of motor symptoms ............................................................................................................................................ 6 Non-motor symptoms ............................................................................................................................................................ 6
Diagnosis of PD ....................................................................................................................................... 7 Neurochemical and neuropathological features of PD ......................................................................... 12 Dopamine ............................................................................................................................................................................ 12 The basal ganglia .................................................................................................................................................................. 15 Degeneration of all DAergic pathways and other systems ................................................................................................... 20 Lewy bodies, Lewy neurites and pale bodies ....................................................................................................................... 21 The six-stage system: a novel neuropathological concept of neurodegeneration ............................................................... 23
Etiology and pathogenesis of PD .......................................................................................................... 25 Genetics of PD...................................................................................................................................................................... 25 Ageing .................................................................................................................................................................................. 27 Role of environmental exposure .......................................................................................................................................... 27 An example of environmental toxin: MPTP................................................................................................................... 27 Other environmental factors ........................................................................................................................................ 29 Metals ........................................................................................................................................................................... 29 Potential theories ................................................................................................................................................................ 30 The “dual-hit” hypothesis ............................................................................................................................................. 30 The “multiple hit or multihit” hypothesis...................................................................................................................... 30 The connection between PD and the FeBAD hypothesis .............................................................................................. 31 Parkinson diseases: a syndrome of different disorders ................................................................................................. 32 Misfolding and aggregation of proteins ............................................................................................................................... 33 Oxidative stress .................................................................................................................................................................... 38 Transition metals: the example of iron ......................................................................................................................... 40 DA metabolism as a source of ROS ............................................................................................................................... 41 Nitric oxide .................................................................................................................................................................... 42 Contribution of oxidative and nitrosative stress to PD pathogenesis ............................................................................ 43 Excitotoxicity ........................................................................................................................................................................ 45 Cell death pathways ............................................................................................................................................................. 48
Experimental models of PD ................................................................................................................... 49 Toxin-induced models .......................................................................................................................................................... 49 6-OHDA ......................................................................................................................................................................... 49 MPTP ............................................................................................................................................................................. 50 Rotenone, paraquat and maneb ................................................................................................................................... 50 Inflammation-based models ................................................................................................................................................ 51 Gene-based models ............................................................................................................................................................. 51
ALUMINIUM.................................................................................................................... 53 General features ................................................................................................................................... 53 Aluminium speciation .......................................................................................................................................................... 53
Sources of aluminium exposure ............................................................................................................ 54 Environmental exposure ...................................................................................................................................................... 54 Dietary exposure .................................................................................................................................................................. 55 Iatrogenic exposure ............................................................................................................................................................. 56 Occupational exposure ........................................................................................................................................................ 56
Aluminium toxicokinetics ...................................................................................................................... 57 Absorption of aluminium ..................................................................................................................................................... 57 Oral absorption .................................................................................................................................................................... 57
Intranasal absorption ........................................................................................................................................................... 58 Dermal absorption ............................................................................................................................................................... 59 Distribution of aluminium in the body ................................................................................................................................. 60 Excretion .............................................................................................................................................................................. 61 Elimination rate ................................................................................................................................................................... 61
Aluminium influx and efflux into the brain ........................................................................................... 62 Putative mechanisms of aluminium neurotoxicity ................................................................................ 63 Aluminium and oxidative stress ........................................................................................................................................... 64 The brain: a target for aluminium ................................................................................................................................. 64 Aluminium catalyses iron-driven biological oxidations ................................................................................................. 65 Aluminium stimulates superoxide-/non-iron-driven biological oxidations ................................................................... 65 Aluminium-superoxide complex theory ........................................................................................................................ 66 Aluminium inhibits the antioxidant enzymes and others .............................................................................................. 66 Aluminium as a cell membrane menace .............................................................................................................................. 67 Aluminium affects cell signaling ........................................................................................................................................... 68
AIMS OF THE PRESENT THESIS ............................................................... 75 OBJETIVOS DE LA PRESENTE TESIS ......................................................... 79 CHAPTER 1 Time-course of brain oxidative damage caused by intrastriatal administration of 6-hydroxydopamine in a rat model of Parkinson’s disease ................................................................ 83 ABSTRACT ....................................................................................................................... 85 INTRODUCTION .............................................................................................................. 86 MATERIALS AND METHODS............................................................................................ 88 Chemicals .............................................................................................................................................. 88 Animal treatment.................................................................................................................................. 88 Brain samples........................................................................................................................................ 89 Determination of TBARS ....................................................................................................................... 89 Determination of protein carbonyl content (PCC) ................................................................................. 89 Determination of protein thiol content (PTC) ....................................................................................... 90 Statistical analysis................................................................................................................................. 91
RESULTS .......................................................................................................................... 92 Effects of 6-OHDA administration on TBARS concentration ................................................................. 92 Effects of 6-OHDA administration on PCC............................................................................................. 92 Effects of 6-OHDA administration on PTC ............................................................................................. 93
DISCUSSION .................................................................................................................... 94
CHAPTER 2 Analysis of brain regional distribution of aluminium in rats via oral and intraperitoneal administration ............. 103 ABSTRACT ..................................................................................................................... 105 INTRODUCTION ............................................................................................................ 106 MATERIALS AND METHODS.......................................................................................... 107 Chemicals ............................................................................................................................................ 107 Animal treatment................................................................................................................................ 107 Brain samples...................................................................................................................................... 108 Electrothermal atomic absorption spectrometry (ETAAS) .................................................................. 108 Statistical analysis............................................................................................................................... 109
RESULTS ........................................................................................................................ 110 Aluminium distribution in the brain after oral and i.p. administration............................................... 110
DISCUSSION .................................................................................................................. 111
CHAPTER 3 Brain oxidative stress and selective behaviour of aluminium in specific areas of rat brain: potential effects in a 6OHDA-induced model of Parkinson’s disease ...................................... 117 ABSTRACT ..................................................................................................................... 119 INTRODUCTION ............................................................................................................ 120 MATERIALS AND METHODS.......................................................................................... 122 Chemicals ............................................................................................................................................ 122 Animal treatment................................................................................................................................ 122 Brain samples...................................................................................................................................... 123 Preparation of brain mitochondria ..................................................................................................... 124 Determination of TBARS, PCC, and PTC .............................................................................................. 124 Measurement of SOD activity ............................................................................................................. 125 Measurement of GPx activity.............................................................................................................. 125 Measurement of CAT activity.............................................................................................................. 126 Determination of MAO activity ........................................................................................................... 126 Immunohistochemistry ....................................................................................................................... 126 Statistical analysis............................................................................................................................... 127
RESULTS ........................................................................................................................ 128 In vivo effects of aluminium administration on brain lipid peroxidation and protein oxidation ....................................................................................................................................... 128 In vivo effects of aluminium administration on the brain activity of different antioxidant enzymes......................................................................................................................................... 128 Effects of aluminium administration on the degeneration of DA terminals in the striatum ......................................................................................................................................... 129 Effects of aluminium administration on brain lipid peroxidation and protein oxidation in 6-OHDA-lesioned rats and controls ............................................................................................... 130 In vitro effects of aluminium on the lipid peroxidation and protein oxidation induced by 6-OHDA autoxidation in brain mitochondrial preparations .......................................................... 131 In vitro effects of aluminium on the enzyme activities of GPx, SOD, CAT, and MAO .......................... 131
DISCUSSION .................................................................................................................. 132
SUMMARY .......................................................................................... 151 CONCLUSIONS ..................................................................................... 157 RESUMEN ............................................................................................ 163 CONCLUSIONES ................................................................................... 169 PUBLICATIONS AS A DIRECT RESULT FROM THIS THESIS ............................................. 175 PUBLICATIONS ARISING FROM COLLABORATIVE WORK DURING THIS THESIS ........... 176
REFERENCES ........................................................................................ 179
INTRODUCTION
INTRODUCTION
INTRODUCTION PARKINSON’S DISEASE
An overview Parkinson‟s disease (PD) was first formally described in modern times in a famous monograph entitled “An essay on the shaking palsy” published in 1817 by an English physician called James Parkinson (Parkinson 1817; Figure 1). In this report, the disease was initially defined as shaking palsy (paralysis agitans) and the syndromes observed were described as “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace: the senses and intellects being uninjured”. Figure 1: An essay of the shaking palsy (Parkinson 1817)
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INTRODUCTION
PD, also called idiopathic PD or primary parkinsonism, is the most common movement disorder besides essential tremor and the second most common age-related neurodegenerative disease after Alzheimer's disease (AD) (Fahn and Przedborski 2000, Tanner and Aston 2000, Mayeux 2003, Fahn and Sulzer 2004). Moreover, PD is the main cause of chronic progressive Parkinsonism accounting for ~80% of cases. Parkinsonism, also known as Parkinson‟s syndrome, atypical Parkinson‟s or secondary Parkinson‟s, is a term which refers to the neurological syndrome characterised by three cardinal motor symptoms: bradykinesia, rigidity and tremor.
Prevalence and incidence of PD More than 4.5 million people worldwide were affected by PD in 2007. Due to increasing life expectancy of the general population and multiplication of effective therapies, the number of individuals over 50 years of age with PD was expected to double to around 9 million patients in the world‟s 10 most populous nations between 2007 and the year 2030 (Dorsey et al. 2007). At the time of writing, PD is affecting approximately 6 million people worldwide. In regards to disease epidemiology, the mean age onset of sporadic PD (also known as idiopathic PD) is 55 years, but is now thought to be in the early-to-mid 60s (Inzelberg et al. 2002). Early onset of PD (EOPD) is rare, about 4% of patients develop clinical signs of the disease before 50 years (Van Den Eeden et al. 2003). Within EOPD, there appear to be two groups namely: young-onset PD (YOPD), with onset between 21 and 40 years, and juvenile Parkinsonism (JP), with onset at <20 years (Muthane et al. 1994). Most prevalence studies of PD across European countries estimated prevalence rates between 1-2/1000 (Von Campenhausen et al. 2005). However PD is observed in approximately 1-2% of the population over 65 years as the incidence increases markedly with advancing age (Louis et al. 1996, de Rijk et al. 1997a, Dauer and Przedborski 2003, Korrell and Tanner 2005). Indeed, the percentage of affected individuals within a population rises ~3-5% at 85 years (Fahn 2003, Onyango 2008). 2
INTRODUCTION
PD is found in all ethnic groups, but with geographical differences in prevalence. Men seem to be slightly more prone to the disorder (Baldereschi et al. 2000, Lai et al. 2003, Benito-León et al. 2004). Incidence rates range from 8.6 to 19.0 per 100,000 inhabitants in the USA and Europe when strict diagnostic criteria of PD are applied (Twelves et al. 2003). Direct comparison of prevalence and incidence estimates are difficult and complicated because of methodological differences between studies (de Rijk et al. 1995, de Rijk et al. 1997b, Benito-León et al. 2003). Stricter diagnosis criteria, record-based studies or studies done in clinical settings yielded lower incidence or prevalence rates than door-to-door surveys or studies with in person examination (Schoenberg et al. 1988, Morgante et al. 1992, Tison et al. 1994, de Rijk et al. 1995, Claveria et al. 2002, Benito-León et al. 2003, Benito-León et al. 2004, de Lau et al. 2004).
Clinical characteristics of PD PD exhibits great variability in clinical presentation as it presents with a range of motor, psychiatric, cognitive, sensory and autonomic symptoms. The three cardinal clinical symptoms of PD include rest tremor, rigidity, and bradykinesia. Often presented as “preclinical PD”, motor and non-motor features that may precede the cardinal motor symptoms by long periods of time should be taken more critically into consideration as they are part of the disease process (Figure 2; Langston 2006). Figure 2: The Parkinson’s complex (Langston 2006)
3
INTRODUCTION
Resting tremor Resting tremor is the most commonly recognized feature of PD and the first motor symptom at disease onset in approximately 75% of PD patients (Jankovic et al. 1990, Hughes et al. 1993, Schrag et al. 2007). However, 25 % of patients with PD never develop tremor (Hughes et al. 1993). Rest tremor has a frequency of 4–6 Hz and classically resembles pill-rolling (descriptive of the rhythmic alternating motion of the forefinger and thumb). This motor manifestation/symptom is usually a supinationpronation tremor, asymmetric, and most prominent in the distal upper extremity as resting foot tremor is much less common than hand tremor as a presenting sign. Tremor at rest is lost during sleep and markedly decreased or abolished with voluntary movement (so typically it does not impair activities of daily living). It should be noted that PD tremor can also be seen to have a postural component. Nevertheless, rest tremor is worsened by excitement, anxiety, apprehension, contralateral motor activity, and is most easily seen when the patient is asked to ambulate with arms hanging at their sides. Observation of the patient during ambulation reveals much about the patient‟s symptoms, including rigidity and bradykinesia.
Rigidity Rigidity is the raised resistance appreciated during the passive movement of the limb about a joint (often of a “lead pipe” quality). A “ratchety” sensation can be noted, indicating the contraction and relaxation of the muscles underlying the tremor. It can have a cogwheel quality even without tremor, but is usually more pronounced in the more tremulous limb. Rigidity is enhanced by contralateral motor activity or mental task performance. Bradykinesia and rigidity are less common then rest tremor but are still frequently seen at onset of PD.
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INTRODUCTION
Bradykinesia Bradykinesia, the most disabling symptom of PD, is easily observed. It results in the slowness in movement and as a consequence significantly impairs quality of life as everyday tasks performance is delayed (eating, dressing, arising from a chair, getting in and out of a car or bed). It initially manifests by difficulties with fine motor tasks (reduced arm swing in walking, speed of handwriting, doing up buttons) and often by decreased blink rate. Various tests can be performed to assess limb bradykinesia, such as fist closing and opening, finger and foot tapping, alternating forearm pronation and supination (Martinez-Martin et al. 1994). Additional motor symptoms are also noticeable as a result of hypokinesia (reduction in movement amplitude) and akinesia (absence of normal unconscious movements) in combination with rigidity, such as micrographia (decreased size of handwriting), reduced stride length in walking, hypophonia (diminished voice volume), dysarthia (slurred speech), hypomimia (facial masking of normal facial expression), and dysphagia (problems swallowing), and sialorrhea (drooling, failure to swallow without thinking about it).
Postural instability Postural instability or the impairment of the righting reflex, sometimes judged a cardinal feature of PD, is non-specific and is less responsive to treatment compared with the others cardinal motor symptoms. Postural instability or gait disturbances refer to the gradual development of poor balance, leading to a high risk for falls and injuries, and sometimes, confinement to a wheelchair. It can be test with the retropulsion test (pulling the patient backward to check for balance recovery). This feature, in combination with rigidity and bradykinesia, results in important disability to the patient. Gait becomes slower, with shuffling, and turning is en bloc (as opposed to pivoting). Freezing is characterised by the inability to begin a voluntary movement such as walking or striking gait hesitation on turning or arriving at a real or perceived obstacle. Postural instability and gait abnormality are not typical at onset of PD. They are usually absent in early
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INTRODUCTION
disease, especially in younger patients, but become a common complication of advanced PD.
Progression of motor symptoms The motor features of tremor and bradykinesia are usually localized to the upper extremities (Uitti et al. 2005). Within one to three years, they extend to the other ipsilateral limb and affect the contralateral limbs in three to eight years (Poewe and Wenning 1998). Despite the fact that PD is almost always a bilateral disease, this asymmetrical pattern remains so throughout most of the course of the illness, even in advances stages (Hughes et al. 2001). As tremor gravity is rather stable over time, whereas severity of bradykinesia and rigidity evolve similarly, some authors hypothesized the existence of different underlying pathophysiological processes (Louis et al. 1999).
Non-motor symptoms Although motor features define PD, various non-motor symptoms, equally significant and potentially disabling, are typically seen. They include autonomic dysfunction (including orthostatic hypotension, bowel and bladder difficulties, abdominal bloating, constipation, urinary urgency and dysfunction, flushing, excessive sweating, temperature dysregulation, and impotence/sexual dysfunction; Jost 2003, Poewe 2008), sensory symptoms (eg. pain, paresthesiae; Quinn et al. 1986), sleep disturbances (REM sleep behaviour disorder, periodic limb movements, etc.; Stacy 2002), psychiatric changes (depression, hallucinations, anxiety symptoms), and cognitive dysfunction (memory deficits, bradyphrenia, executive function difficulty, dementia; Levin and Katzen 2005, Rippon and Marder 2005, Caviness et al. 2007). Depression is common in PD, as it develops in about 50% of individuals with PD (McDonald et al. 2003). Dementia is significantly more frequent in PD, especially in older patients, ranging from 40-80% of patients (Cedarbaum and McDowell 1987, Emre 2003, Poewe 2008). Non-motor symptoms, present with considerable variability, may
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INTRODUCTION
predate the occurrence of motor symptoms and should be recognized and treated as soon as possible to maximize functionality as well as quality of life.
Diagnosis of PD The diagnosis of PD is essentially made on clinical criteria. Whereas these clinical criteria lead, at best, to a diagnosis of probable PD, post-mortem confirmation is required to establish a definite diagnosis of PD (Hughes et al. 1992a, Koller 1992). Historically, the identification of Lewy bodies (LB) on autopsy was considered the criterion standard for diagnosis (Gibb and Lees 1988). A diagnosis of primary parkinsonism requires at least the presence of two of the primary cardinal motor symptoms (resting tremor, bradykinesia, rigidity) and exclusion of potential causes of secondary parkinsonism. The following features are considered by most experts as essential and the most important to discriminate PD from other diagnoses: a unilateral or asymmetrical onset of motor symptoms and a consistent response of the symptoms to an adequate dose of a dopaminergic (DAergic) agent such as levodopa given for a sufficient period. If it is not the case, an alternative diagnosis should be assumed. The differential diagnosis of PD includes normal ageing, essential tremor, and other parkinsonian syndromes such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and vascular parkinsonism, amongst others (Stoessl and Rivest 1999; Table 1). The diagnosis of PD is difficult especially on early-stages of the disease, because atypical features may be absent or insignificant and there is no information on levodopa-responsiveness. A long-term follow-up of patients is needed to revise diagnoses on the basis of information on disease progression, physical examination, improvement/emergence of other symptoms and responsiveness to DAergic treatment. Post-mortem studies demonstrated misdiagnosis in up to 25% of patients diagnosed with PD by general neurologists as their brain reveal no pathological sign of the disease (Rajput et al. 1991, Hughes et al. 1992a). It is worth noting that accuracy of PD
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INTRODUCTION
diagnosis was substantially higher in patients diagnosed by experts in movement disorders (Hughes et al. 2002). In order to improve diagnostic accuracy, revised and more stringent diagnostic criteria were developed by the UK Parkinson‟s Disease Society Brain Bank (Table 2) (Hughes et al. 1992b) and the National Institute of Neurological Disorders and Stroke (NINDS) (Table 3) (Gelb et al. 1999). Nevertheless they still remain controversial as clinicopathological studies suggest that about 10-20% of PD cases remain as false positives (Hughes et al. 2001, Litvan et al. 2003). The problem is that a reliable and easily valid diagnostic test for PD is not yet available. When there is doubt about the diagnosis or when the patient‟s history or clinical findings are atypical, sophisticated neuroimaging techniques may be useful to differentiate PD from other diseases (Piccini and Brooks 2006). Conventional brain imaging, such as magnetic resonance imaging (MRI) or computarized tomography (CT), are helpful when normal pressure hydrocephalus or vascular parkinsonism are suspected (Demirkiran et al. 2001). Sophisticated imaging techniques of the DA pathways such as positron emission tomography (PET) or single photon emission computarized tomography (SPECT), can make a distinction of PD from essential tremor,
dystonic
tremor,
neuroleptic-induced
parkinsonism
and
psychogenic
parkinsonism/postsynaptic forms of parkinsonism in specialised settings (Vingerhoets et al. 1994, Lee et al. 2000, Winogrodzka et al. 2001, Piccini and Brooks 2006). Although these promising techniques have become more widely available and easier to use, much controversy exists (because of the lack of universally accepted neuropathological criteria for PD) (Clarke and Gutman 2002, Marek et al. 2002, Litvan et al. 2003). Usefulness for population epidemiological studies is still limited as sensitivity and resolution of these neuroimaging techniques need to be improved and refined.
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INTRODUCTION
Table 1:
Differential diagnostic in parkinsonian disorders (Alves et al. 2008)
Parkinson’s diseasea
Idioptahic Familial
Symptomatic parkinsonism
Drug-induced Neuroleptics, antidepressants, lithium Antiemetics Antihypertensive agents, antiarrhythmics Vascular disease Intoxication (MPTP, rotenone, others) Traumatic Post-infectious Neoplasm Normal pressure hydrocephalus
Parkinsonism due to other neurodegenerative disorders
Atypical parkinsonism Multiple system atrophy (MSA)a Progressive supranuclear palsy (PSP)b Corticobasal degeneration (CBD)b Dementia with Lewy bodies (DLB)a Alzheimer’s diseaseb (AD) Others
a
synucleinopathy; b tauopathy
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INTRODUCTION
Table 2:
UK Parkinson’s Disease Society Brain Bank’s diagnostic criteria for the diagnosis of probable PD (Jankovic 2008, Davie 2008)
Step 1: Diagnosis of a parkinsonian syndrome Bradykinesia, and at least one of the following criteria: Muscular rigidity 4-6 Hz rest tremor Postural instability (not caused by primary visual, vestibular, cerebellar or propioceptive dysfunction) Step 2: Exclusion of other causes of parkinsonism i ii iii iv v vi vii viii ix x xi xii xiii xiv xv
History of repeated strokes with stepwise progression of parkinsonian features History of repeated head injury History of definite encephalitis Oculogyric crises Neuroleptic treatment at the onset of symptoms More than one affected relative Sustained remission Strictly unilateral features after 3 years Supranuclear gaze palsy Cerebellar signs Early severe autonomic involvement Early severe dementia with disturbances of memory, language and praxis Babinski’s sign Presence of cerebral tumour or communicating hydrocephalus on CT scan Negative response to large doses of levodopa (if malabsorption excluded)
Step 3: Supportive (prospective) criteria for PD (at least three or more required for diagnosis of definite PD) i ii iii iv v vi vii viii
10
Unilateral onset Rest tremor present Progressive disorder Persistent asymmetry affecting side of onset most Excellent response (70–100%) to levodopa Severe levodopa-induced chorea (dyskinesia) Levodopa response for 5 years or more Clinical course of 10 years or more
INTRODUCTION
Table 3:
National Institute of Neurological Disorders (NINDS) diagnostic criteria for PD (Jankovic 2008)
Group A features (characteristic of PD) Resting tremor Bradykinesia Rigidity Asymmetric onset
Group B features (suggestive of alternative diagnoses) Features unusual early in the clinical course Prominent postural instability in the first 3 years after symptom onset Freezing phenomenon in the first 3 years Hallucinations unrelated to medications in the first 3 years Dementia preceding motor symptoms or in the first year Supranuclear gaze palsy (other than restriction of upward gaze) or slowing of vertical saccades Severe, symptomatic dysautonomia unrelated to medications Documentation of condition known to produce parkinsonism and plausibly connected to the patient’s symptoms (such as suitably located focal brain lesions or neuroleptic use within the past 6 months)
Criteria for definite PD All criteria for probable Parkinson’s are met and Histopathological confirmation of the diagnosis is obtained at autopsy
Criteria for probable PD At least three of the four features in group A are present and None of the features in group B is present (note: symptom duration >3 years is necessary to meet this requirement) and Substantial and sustained response to levodopa or a dopamine agonist has been documented
Criteria for possible PD At least two of the four features in group A are present; at least one of these is tremor or bradykinesia and Either none of the features in group B is present or symptoms have been present (3 years and none of the features in group B is present and Either substantial and sustained response to levodopa or a dopamine agonist has been documented or the patient has not had an adequate trial of levodopa or a dopamine agonist
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INTRODUCTION
Neurochemical and neuropathological features of PD Dopamine Dopamine (DA) plays important roles in control movement, motivation and reward, behaviour and cognition, mood, sleep, attention and learning. This biogenic monoamine is synthesized in the catecholaminergic neurons from L-tyrosine. First, tyrosine hydroxylase (tyrosine 3-monooxygenase, TH) converts L-tyrosine to 3,4dihydroxy-L-phenylalanine (L-DOPA). TH requires 5,6,7,8-tetrahydrobiopterin (BioH4) as a coenzyme (Agid 1991). The second step is catalyzed by the DOPA decarboxylase (aromatic L-amino acid decarboxylase, AADC), L-DOPA is decarboxylated to DA (Figure 3). In some neurones, beta-hydroxylase processes DA into noradrenaline, which is metabolized to adrenaline by phenylethanolamine N-methyltransferase. DA is degraded by catechol-O-methyl transferase (COMT), aldehyde dehydrogenase (ADH) and monoamine oxidase (MAO) (Figure 4). MAO-A and -B also degrade other monoamines including serotonin, noradrenaline, and adrenaline. Figure 3: Dopamine synthesis (Méndez-Álvarez and Soto-Otero 2004) O2 NH3
H2O
tyrosine hydroxylase
HO
aromatic L-amino acid decarboxylase (pyridoxal phosphate)
COO
COO HO
HO
L-tyrosine H2N
N
HN O
3,4-dihydroxy-L-phenylalanine (L-DOPA)
H N N H
CH CH CH3 OH OH
5,6,7,8-tetrahydrobiopterin (BioH4) NAD
dihydrobiopterin reductase NADH + H
12
NH3
HN
N
CO2
H N
HO
NH3
HO
HN
N O
CH CH CH3 OH OH
quinonoid dihydrobiopterin (BioH2)
dopamine (DA)
INTRODUCTION
Figure 4: Dopamine catabolism (Méndez-Álvarez and Soto-Otero 2004) HO
CHO
H 2O 2
H2O + NAD
HO
monoamine oxidase O2
aldehyde dehydrogenase 3,4-dihydroxyphenylacetaldehyde (DOPAL)
NADH + H
NH4 HO
NH3
H 2O
HO
COO
HO
HO
dopamine (DA)
catechol-O-methyltransferase CH3 O
3,4-dihydroxyphenylacetic acid (DOPAC) NH2
COO
HO
homovanillic acid (HVA)
NH2 N
N S CH2 CH2 O S-adenosyl-homocysteine CH 2 (SAH) CH NH3 OH OH COO
N N
N CH3 N CH2 S CH2 O CH2 CH NH3 OH OH COO
N N
S-adenosyl-methionine (SAM)
DA is a neurotransmitter widely distributed throughout the whole brain, but mostly localized in the striatum. It is produced by mesencephalic neurons of the substantia nigra (SN) and ventral tegmental area (VTA), and by hypothalamic neurons of the arcuate and periventricular nuclei (Cooper et al. 1996). DAergic neurons located in these areas project their axons to the striatum (nigrostriatal pathway), neocortex (mesocortical pathway), limbic system (mesolimbic pathway) and hypophysis (tuberoinfundibular pathway) (Figure 5). DA receptor family consists of five members divided into two subfamilies: the D1-like family comprises D1 and D5 receptors, whereas the D2-like family includes D2, D3 and D4 receptors (Cooper et al. 1996, Jackson and Westlind-Danielsson 1994). D1 receptors are widely expressed in the brain, whereas D2 receptors are principally seen in the striatum and nucleus accumbens (Figure 6). As we will discuss later, DA plays a central role in the pathology of PD as this neurotransmitter is crucial for basal ganglia regulation.
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INTRODUCTION
Figure 5: Dopamine pathways (CNSforum www.cnsforum.com)
Figure 6: Distribution of DA receptors in normal brain (CNSforum www.cnsforum.com)
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INTRODUCTION
The basal ganglia The basal ganglia (BG) constitute mainly five subcortical nuclei located deep in the hemispheres: the substantia nigra with its pars compacta (SNpc) and pars reticularis (SNpr), the striatum (caudate nucleus and putamen), the internal and external segments of globus pallidus (GPi and GPe), and the subthalamic nucleus (STN) (Figure 7). The BG form a complex network of anatomically and functionally segregated loops involved in the regulation of emotional and cognitive functions and particularly in the control of cortically initiated motor activity, which if disturbed leads to some form of movement disorder. Figure 7: The basal ganglia (Society for Neuroscience www.sfn.org)
These parallel loops have been functionally subdivided into motor, oculomotor, limbic, association and orbitofrontal loops (Alexander et al. 1986, Alexander and Crutcher 1990, Middleton and Strick 2000). The striatum is the primary input structure of BG as it receives excitatory glutamatergic signals from many areas of the sensory motor cortex and thalamus, as well as a dense innervation from midbrain DA neurons. The most abundant striatal neurons are striatonigral and striatopallidal neurons
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INTRODUCTION
accounting each for approximately 49% (Rymar et al. 2004). The firsts exhibit high expression of D1 receptors and send axons to the main output nuclei of BG for movement control, GPi and SNpr, while the latters contain high expression of D2 receptors and innervate directly GPe. In the classical model of BG circuitry, the motor loop integrates two distinct routes identified as “direct” and “indirect” pathways which proceed from the striatum, especially from the putamen, and that act in opposing ways to control movement (Albin et al. 1989, Alexander and Crutcher 1990, DeLong 1990). The “direct” pathway facilitates voluntary movement. Striatonigral neurons project to GABAergic neurons in GPi and SNpr, which in turn send axons to the motor nuclei of the thalamus. As the neurotransmitter of both projections (striatum to GPi/Snpr, and Gpi/SNpr to thalamus) is -aminobutyric acid (GABA), which is inhibitory, the net effect of the direct pathway activity is a disinhibition of excitatory thalamocortical projections, resulting in activation of cortical premotor circuits and facilitation of movement. On the other hand, the “indirect” pathway originates in striatopallidal neurons that project to GPe providing an inhibitory effect. This region in turn sends axons to the STN (disinhibition) which provides outflow to GPi and SNpr (excitation) enhancing the inhibitory effect of the BG output nuclei on thalamocortical neurons, thus reducing movement (Figure 8). Figure 8: Direct and indirect pathway in normal BG circuits, sagittal view of a mouse brain (Kreitzer and Malenka 2008)
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INTRODUCTION
The death of SNpc DAergic neurons The main pathological biochemical hallmark of PD is the death of DAergic neurons residing in the ventral midbrain nucleus, called the SNpc. The cell bodies of the SNpc neurons project primarily to the putamen and upward to the caudate nucleus composing the nigrostriatal pathway. The loss of these neurons which contain considerable amounts of neuromelanin leads to the neuropathological finding of SNpc depigmentation (Figure 9; Marsden 1983). Consequently the death of nigrostriatal DAergic neurones results in a loss of the neurotransmitter DA in the striatum, more precisely in the dorsolateral putamen where the depletion of DA is most pronounced (Bernheimer et al. 1973). This leads to the main motor features of PD as the striatum integrates signals from the motor cortex and regulates neural circuits within the BG to control movement. Furthermore this agrees well with the correlation between the pattern of SNpc cell loss and the expression levels of the DA transporter (DAT) mRNA (Figure 10; Uhl et al. 1994). Figure 9: SNpc depigmentation, appearance of normal (left) and Parkinsonian (right) human midbrain (National Center for Biotechnology Information www.ncbi.nlm.nih.org)
At the onset of symptoms, approximately 60% of the SNpc DAergic neurones and 80% of DA content in putamen have already been lost (Fearnley and Lees 1991, Deumens et al. 2002). This suggests that neuronal death in PD may result from a “dying back” process as the striatal DAergic nerve terminals seem to be the primary target of neurodegeneration before subsequent cell body effects (Dauer and Przedborski 2003). DA depletion causes a cascade of functional changes in BG circuitry as it leads to
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INTRODUCTION
reduced activity in the “direct” pathway and increased activity in the “indirect” pathway, resulting in excessive GPi/SNpr inhibitory output to the thalamus (Figure 11). These changes lead to a hypokinetic disorder characterized by inhibition of movement (Kreitzer and Malenka 2008). Figure 10: Human brain sections immunostained for DAT of normal person (A) and PD patient (B) (Betarbet et al. 2002)
Neuroimaging and pathological studies suggest that there is a long latency between nigral degeneration begin and symptoms onset. The presymptomatic latent phase was estimated to be approximately 6 years in idiopathic PD and longer in familial PD (Fearnley et al. 1991, Morrish et al. 1996, Hilker et al. 2005). This long asymptomatic period indicates that compensatory mechanisms are able to deal with progressively lower DA levels in order to preserve apparent normal BG function. These compensatory mechanisms which comprise increased striatal DA turnover and receptor sensitivity, upregulation of striatopallidal enkephalin levels, increased subthalamic excitation of GPe, and maintenance of cortical motor area activation (Bezard et al. 1999, Bezard et al. 2001), might be potentially damaging to nigral neurons through rising cellular metabolic demand, oxidative stress, and excitotoxicity (Rodriguez et al. 1998, Jenner 2003). The PD-associated cell loss has a characteristic topology distinct from the pattern seen in the course of normal aging of the human organism as the SN is characterized by a low level of neuronal degeneration (Kubis et al. 1995). Furthermore, normal aging-related morphological modifications were found to be most intensive in
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INTRODUCTION
the dorsomedial part of SNpc while in PD the ventrolateral and caudal portions of SNpc are particularly affected (Fearnley and Lees 1991). Figure 11: Classical model of the BG in the normal state (A) and parkinsonian state (B) (Obeso et al. 2008)
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INTRODUCTION
Degeneration of all DAergic pathways and other systems Although the nigrostriatal pathway is the most severely affected in PD, all ascending DAergic pathways in the central nervous system (CNS) do degenerate although to variable degrees (reviewed by Hornykiewicz and Kish 1987). The mesolimbic DAergic neurons which reside adjacent to the SNpc in the VTA and connect with the ventral striatum are less affected in PD: they are decreased between 37-50% of that in healthy subjects (Price et al. 1978, Javoy-Agid and Agid 1980, Uhl et al. 1985, Dymecki et al. 1996). As a result, there is significantly less DA depletion in the caudate nucleus (Price et al. 1978), the main site of projection for these neurons. It is important to stress that PD not only affects the DAergic nerve cells of the SN but also other areas and neurotransmitter systems: noradrenergic (locus coeruleus (LC), where cell loss may exceed that seen in SNpc; Zarow et al. 2003), cholinergic (nucleus basalis of Meynert, NBM; dorsal motor nucleus of vagus, DMV), and serotonergic (dorsal raphe nuclei). Pathological changes are also observed in glutaminergic, tryptaminergic, GABAergic, and adrenergic neurons (Braak and Braak 2000). Besides, cell loss is seen in other regions: postganglionic sympathetic neurons and cortex (especially cingulate and entorhinal cortices), olfactory bulb, and autonomic nervous system (Braak et al. 1995, Braak and Braak 2000, Levy 2009). Interestingly, the loss of non-DAergic neurons, especially in the caudal brainstem, may even become involved before the DAergic neurons (Braak et al. 2006). Thus, PD symptoms are the consequence of progressive degeneration of the DAergic neuronal BG system but also of other ascending subcortical neuronal systems. Whereas the main motor manifestations of PD are linked to neurodegeneration in the DAergic systems, the non-DAergic pathways degeneration likely contributes as a major cause of many of the non-motor symptoms of PD, such as depression, cognitive decline, constipation and autonomic dysfunction. As an example, degeneration of cholinergic cortical inputs and hippocampal structures are part of the cause of the high rate of dementia that accompanies PD, especially in older persons. As the clinical correlates of lesions of these non-DAergic neurotransmitters pathways are not as clearly
20
INTRODUCTION
characterized as are lesions in the DAergic systems, the temporal relationship of damage to specific neurochemical systems is not well established. Although, for example, some patients develop depression months or years prior to the onset of motor symptoms, the non-motor symptoms are generally thought to dominate the more severe or later stages of the disease (Chaudhuri et al. 2006).
Lewy bodies, Lewy neurites and pale bodies In addition to neuronal loss, another important pathological feature observed in PD is the presence of fibrillar aggregates, called LB, Lewy neurites (LN) and pale bodies, in the few remaining surviving nigral DAergic neurons (Dauer and Przedborski 2003, Probst et al. 2008). There are two morphologic types of LB: the brainstem classical type and the cortical type. Brainstem-type LB are intraneuronal cytoplasmic inclusions, spherical or elongated, 5-25 μm in diameter, and possessing a dense eosinophilic core and a clear peripheral halo (Figure 12A; Duffy and Tennyson 1965, Roy and Wolman 1969, Pappolla 1986). Cortical LB are also intracytoplasmic inclusions but often irregular in shape and lacking a distinctive core and conspicuous halo Figure 12B. LN correspond to abnormal dystrophic neurites that contain filaments similar to those found in LB (Figure 12C; Dickson et al. 1991). Whereas LB are developed in the perikarya, LN are located in the neuronal processes (Figure 12D). Pale bodies are rounded well-defined areas without halos, less eosinophilic, found in melanized cells of the SNpc and the locus coeruleus. They contain vesicular and granular structures and filaments identical to those seen in LB. As pale bodies often co-occur with one or more LB in the same neurons, they have been proposed to represent a stage in the formation of LB. LB are composed of more than 76 molecules, including numerous proteins, such as α-synuclein, parkin, ubiquitin, and neurofilaments (Wakabayashi et al. 2007). Whereas the SNpc appears to be the first region to be affected by neuronal loss, LB are not confined to the SNpc but can also be found within many of the spared neurons in
21
INTRODUCTION
other brain areas and in the peripheral autonomic nervous system as the disease progresses (Forno et al. 1996, Wakabayashi and Takahashi 1997, Spillantini et al. 1998, Braak et al. 2003, Wakabayashi et al. 2007). The extensive distribution of LB could account for a variety of motor and non-motor symptoms of PD. Interestingly it has been proposed that LB appear first in both the olfactory bulb and lower brain stem, following then a foreseeable progression which contributes to explain the loss of olfaction which might precede motor symptoms. Figure 12: LB and LN in PD patients (A, B: Wakabayashi and Takahashi 2007, C: Braak and Del Tredici 2008) and localization of LB and LN (D: Braak et al. 2003) A
B
C
D
The presence of LB is not specific for PD as they occur also in AD, dementia with LB (DLB) and in healthy people of advanced age at a greater frequency than the prevalence of PD (Gibb and Lees 1988). The role of LB in neuronal cell death is controversial and under debate: LB may be toxic by interfering with normal cellular processes and/or by sequestering important proteins for cell survival or on the other hand, they could be cytoprotective as they may sequester and degrade the toxic proteins
22
INTRODUCTION
(Olanow et al. 2004). Most likely, LB seem to be symptomatic in PD pathogenesis, not causative (Wakabayashi et al. 2007).
The six-stage system: a novel neuropathological concept of neurodegeneration Recently, Braak and colleagues established a staging procedure based on the distribution of LB and LN (Braak et al. 2003, Braak et al. 2006). According to the pathological changes observed during the cross-sectional study originally performed on autopsy cases, the authors proposed that the formation of proteinaceous intraneuronal LB and LN follows a topographically predictable sequence in six stages with ascending progression from medullary and olfactory nuclei to the cortex (Figure 13). In early stages 1 and 2, patients are pre-symptomatic. LB pathology first appears in the dorsal motor nucleus of the vagal nerve and is confined to the medulla oblongata, pontine tegmentum and anterior olfactory structures. As the disease advances, in stages 3 and 4, pathological changes appear in the SN and in other areas of the basal midbrain and forebrain. Motor symptoms become clinically manifest during this phase. Finally the final stages 5 and 6 are frequently associated with cognitive impairment as the neocortex becomes involved (Figure 14). Many groups give strong support to this neuropathological concept which states that neurodegeneration in PD starts in non-DAergic areas, notably the enteric nervous system and then rises via spinal cord and brainstem to nigral and subsequent cortical neurons (Abbott et al. 2001, Przuntek et al. 2004, Abbotth et al 2005, Ross et al. 2005, Ross et al. 2006). Nevertheless, it has also been brought into question as some neuropathological studies showed brains with important neurodegeneration and αsynuclein pathology in the SNpc and higher brain structures but lacking medullary involvement (Parkinnen et al. 2003, Jellinger 2004, Parkinnen et al. 2005, Attems and Jellinger 2008, Dickson et al. 2008, Kalaitzakis et al. 2008a, 2008b, Parkinnen et al. 2008).
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INTRODUCTION
Figure 13: Six stages of brain pathology in idiopathic PD (Braak et al. 2003)
Figure 14: Stages 3–6 of pathological changes associated with sporadic PD in hemisphere sections immunostained for -synuclein (Braak et al. 2006)
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INTRODUCTION
Etiology and pathogenesis of PD The cause of most cases of PD remains unclear. By the date several pathogenic mechanisms based on environmental, genetic and histopathological findings have been implicated in this disease. They may be primary activating events for the disease and secondary events involved in promoting progression of PD over time. The contributions of genetic and environmental risk factors and the impact of compensatory mechanisms on PD progression are still unanswered questions. Some forms of PD have been associated to specific environmental causes (Langston et al. 1983, Thrash et al. 2007, Jang et al. 2008), while a few familial forms of PD and related parkinsonism are related to apparent genetic causes (Biskup et al. 2008, Gasser 2009).
Genetics of PD In the majority of PD cases, there is no apparent genetic linkage and the disease is referred to as “sporadic” or idiopathic PD. Thus, familial cases only represent a 510% of the whole affected population. The disease is inherited and defined by at least one relative (parent or sibling) also having PD. It is not always clear if this is due to heritable genetic factors or shared environment. But an inherited genetic contribution was put forward by various studies, mono- and dizygotic twins and families with PD history (Tanner 1999, Thacker and Ascherio 2008). An increasing number of single gene mutations causing familial PD have been identified (Table 4). They show both autosomal dominant and recessive as well as Xlinked modes of inheritance (Vila and Przedborski 2004, Wood-Kaczmar et al. 2006). Many of these have also been found in apparently sporadic cases (Warner and Schapira 2003) suggesting that they may act as susceptibility factors. Chromosomal regions have been designated as “PARK” genes. These include two autosomal dominant genes: synuclein (SNCA) (Polymeropoulos et al. 1997, Krüger et al. 1998) and leucine-rich repeat kinase 2 LRRK2 (Paisán-Ruiz et al. 2004, Zimprich et al. 2004), and three autosomal recessive genes: parkin (PRKN) (Kitada et al. 1998), PTEN-induced putative
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INTRODUCTION
kinase 1 (PINK1) (Valente et al. 2004), and DJ-1 (Bonifati et al. 2003). New and crucial insights into the PD pathogenesis have been supplied by the discovery of these genetic mutations and the improved comprehension of dysfunction of their abnormally encoded proteins.
Gene loci associated with PD (*Toulouse and Sullivan 2008, #Schapira 2008)
Table 4:
a
Locus (MIM#)
Inheritance
Chromosomal location
Gene
Onset
Clinical features
Neuropathology
PARK1 (168601)
AD
4q21
SNCA (mutations)
Mid-late
Nigral degeneration, with LB
PARK2 (600116)
AR
6q25.2–q27
Parkin
Early
PARK3 (602404)
AD
2p13
Not known
Late
PARK4 (605543)
AD
4q21
SNCA (duplication / triplication)
Late
PARK5 (191342)
AD
UCHL1
Mid-late
PARK6 (605909)
AR
* 4p14 # 4p15 * 1p36 # 1p35
Idiopathic PD, low incidence of tremor, fast progression Drug induced dyskinesia, dystonia, slow progression Idiopathic PD, dementia, fast progression Dementia, autonomic dysfunction, postural tremor, fast progression Idiopathic PD
PINK1
Early
Not reported
PARK7 (606324)
AR
1p36
DJ1
Early
PARK8 (607060)
AD
* 12q12 # 12p12
LRRK2
Late
Slow progression, drug-induced dyskinesia Slow progression, psychiatric symptoms Idiopathic PD
PARK9 (606693)
AR
* 1p36 # 1p32
ATP13A2
Juvenile
PARK10 (606852) PARK11 (607688) PARK12 (300557) PARK13 (610297) (601828) (603779)
AD
Not known
Late
AD
* 1p # 1p32 2q36–q37
Spasticity, supranuclear gaze paralysis, dementia Not reported
Not known
Late
Not reported
Not reported
X-linked
Xq21–q25
Not known
Not reported
Not reported
AD
2p12
Htra2
Not reported Late
Idiopathic PD
Not reported
2q22–q23 5q23.1–q23.3
NR4a2 Synphilin1
Late Late
Idiopathic PD Idiopathic PD
Not reported Not reported
b
a b
LB: Lewy bodies, NFT: neurofibrillary tangles, plaques: amyloid plaques. PARK9 initially presented as idiopathic PD but is now known as Kufor–Rakeb syndrome.
26
Nigral degeneration, without LB Nigral degeneration, with LB, NFT and plaques Nigral degeneration, with LB, vacuoles in neurons
* Not reported # Yes
Not reported
Nigral degeneration, variable features including LB, NFT and ubiquitinated inclusions Striatal atrophy
Not reported
INTRODUCTION
Ageing Ageing remains an important risk factor of PD. It is associated with a decline of pigmented neurons in the SNpc (McGeer et al. 1977) and a decline in striatal DA transporters (Van Dyck et al. 2002) but no difference between the caudate and putamen as seen in PD. Even if the incidence of PD is known to increase with age, this disease is not a simple acceleration of ageing as the pattern of neuronal loss in SN in PD patients and in the normal aging population differs substantially (Kish et al. 1992).
Role of environmental exposure Exposure to environmental factors may strongly influence risk of PD. Environmental factors have also been implicated in the pathogenesis of PD with varying degrees of association. These include environmental toxins, occupation, dietary factors, drug use and metals amongst others.
An example of environmental toxin: MPTP The environmental toxin hypothesis considers that PD-related neurodegeneration is a consequence from exposure to a DAergic neurotoxin. MPTP (1-methyl-4-phenyl1,2,3,6-tetrahydropyridine) is a prototypic example of how an exogenous toxin can mimic the clinical and pathological features of PD. Davis et al. (1979) and Langston et al. (1983) were the first to convincingly demonstrate the link between environmental toxin exposure and the development of PD. They observed that, after illicit drug consumption, a series of patients developed physical symptoms consistent with PD, and acute levodopa-responsive parkinsonism. In one case, substantial damage to nigral neurones was observed (Davis et al. 1979). Analysis of the drug used revealed a contamination with two side products, MPTP and MPPP (1-methyl-4-phenyl-4propionoxy-piperidine) in the synthesis of a meperidine analogue (Langston and Ballard 1983). The causative link between MPTP and the parkinsonian syndrome observed in
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INTRODUCTION
the drug users was further confirmed by the development of symptoms very similar to PD following injection of MPTP in an animal model (Burns et al. 1983). Studies showed that MPTP readily crosses the blood-brain barrier (BBB) and is oxidized by MAO-B in astrocytes within glia to a pyridinium derivative, MPP+ (1methyl-4-phenyl pyridinium ion) (Ransom et al. 1987). MPP+ is then selectively taken up by the DAergic cells and accumulated in nigrostriatal neurons (Chiba et al. 1985). After entering the mitochondria by the passive cationic gradient, MPP+ inhibits the NADH-dehydrogenase at complex I in the respiratory chain preventing ATP synthesis and leading to reactive oxygen species (ROS) production and cell death in DAergic neurons (Chiba et al. 1984, Heikkila et al. 1985, Nicklas et al. 1985, Vyas et al. 1986, Singer and Ramsay 1990) (Figure 15). Studies showed that pre-treatment of animals with two selective MAO-B inhibitors (deprenyl or pargyline), blocked MPTP toxicity most likely by blocking MPTP oxidation to MPP+ (Heikkila et al. 1984, Langston et al. 1984, Markey et al. 1984). Figure 15: MPTP metabolism (Dauer and Przedborski 2003)
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INTRODUCTION
The finding of MPTP toxicity not only established a link between environmental exposure and the development of PD, but also introduced MPTP as experimental model for the study of PD. Other DAergic neurotoxins have been identified, such as the insecticide rotenone and the herbicide paraquat (Brooks et al. 1999, Betarbet et al. 2000, Dhillon et al. 2008, Cannon et al. 2009). As MPTP, paraquat and rotenone are selective complex I inhibitors and induce DA diminution in animal studies. This will be discussed later in the section “Experimental models of PD”.
Other environmental factors Since the discovery of MPTP-induced parkinsonism, many epidemiological studies have been performed to examine the link between the risk of PD and other environmental factors. Lifestyle-associated factors can have positive or negative influence on the risk of developing PD. Living in a rural environment (in industrialised countries), farming, exposure to pesticide use and wood preservatives, and drinking well water (Hertzman et al. 1990, Engel et al. 2001, Priyadarshi et al. 2001, Baldiet al. 2003, Gorell et al. 2004, Dick 2006) seem to confer an increased risk of PD but it remains debatable (Koller et al. 1990, Gorell et al. 1998). On the contrary, some environmental factors appear to exhibit a negative correlation with PD. Caffeine intake, cigarette smoking, and high vitamin intake are inversely associated with the risk of developing this disease (Baron 1986, Morens et al. 1995, Ross et al. 2000, Hernan et al. 2002, Lai et al. 2002, Landrigan et al. 2005, de Lau and Breteler 2006).
Metals Exposure to some specific metals such as aluminium, amalgam, copper, iron, lead, manganese, mercury, zinc, and a combination of metals have also been hypothesised to be a risk factor in PD through the accumulation of metals in the SN and increased oxidative stress (Ngim and Devathasan 1989, Zayed et al. 1990, Seidler et al. 1996, Gorell et al. 1997, Gorell et al. 1999, Rybicki et al. 1999, Kuhn et al. 1998, Lai et al. 2002). During the past few years, special attention was paid to aluminium. As it will
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INTRODUCTION
be largely discussed later, its ubiquity and extensive use in products and processes coupled with its reported ability to cause neurodegeneration have made aluminium a cause of health concern (Exley 1999, Yokel 2000, Zatta et al. 2003, Kawahara 2005).
Potential theories Experimental
models
of
PD,
epidemiologic
studies,
neuropathologic
investigations, and genetic analyses, which implicated both environmental and genetic factors in the pathogenesis of PD, provided important insights into the pathogenesis of PD (Beal 2001, Betarbet et al. 2002, Dawson and Dawson 2003, Siderowf and Stern 2003). But the exact causative pathogenic pathway(s) for the development of PD remain(s) hard to demonstrate. Several hypotheses aiming to explain the cause and beginnings of PD have been proposed.
The “dual-hit” hypothesis The “dual-hit” hypothesis proposed that a hitherto unknown neurotrophic pathogen induces the pathological process causing PD and triggering the sequential involvement of vulnerable regions (Hawkes et al. 2007). This pathogen may enter the brain via two routes: nasal, with anterograde progression to the amygdala and temporal lobe; or gastric, by subsequent retrograde and transneuronal transport.
The “multiple hit or multihit” hypothesis The “multiple hit or multihit” hypothesis points to the idea that PD, originally identified as a DA-deficit disorder, is probably a multietiological disease resulting of the combination of multiple interlinking combinated factors or insults acting together (Sulzer 2007). As assumed by Lang and colleagues, a disease with various contributing etiologic issues could have several diverse ways of onset and progression (Lang et al. 2007) and this could explain the interindividual clinical and neuropathological heterogeneity observed in the course of PD. It is important to note that this supposition
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INTRODUCTION
may clarify why many neuropathologic studies did not conform to the six-stage Braak system and why some patients present obvious non-DAergic features while others have little difficulty with these over a prolonged disease course. The connection between PD and the FeBAD hypothesis Also, Barlow and colleagues recently explored the possibility to link PD with the fetal basis of adult disease (FeBAD) hypothesis. They proposed that environmental stressors encountered very early in life (in utero or during the perinatal period) may decrease the number of DAergic neurons making the nigrostriatal system vulnerable to subsequent insults or to a failure of normal compensatory mechanisms (Figure 16; Barlow et al. 2007). Indeed, even if PD is considered as an age-related disorder, the biology of this disease may start decades prior to the critical treshold of 60% neuronal loss or clinical manifestations. Figure 16: The multiple hit model of PD (Barlow et al. 2007)
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INTRODUCTION
Parkinson diseases: a syndrome of different disorders There is a large body of evidence indicating that impairment in protein biology, mitochondrial dysfunction, neuroinflammation, cell death pathways, excitotoxicity, and oxidative stress, to cite only some of the most salient, are key pathologic mechanisms in the etiology of PD, all of which are tightly linked (Figure 17; Mattson 2000, Chung et al. 2001, Vila and Przedborski 2003, Eriksen et al. 2005, Gandhi and Wood 2005, Abou-Sleiman et al. 2006, Olanow 2007, Tansey et al. 2007). But none of these pathogenic mechanisms alone has been proven to be the exact causative and unifying cytotoxic pathway leading to neurodegeneration in PD (Sulzer 2007). It is now widely recognized that PD is not a single homogenous disease but to a certain extent a multifaceted syndrome of different neurological disorders, caused by a complex interaction between genetic, environmental, and other factors leading to a common final pathology (Moore et al. 2005, Klein and Schlossmacher 2007, Schapira 2008, Zhou et al. 2008). Actually, the term Parkinson diseases was proposed to reassess this syndrome of multiple “parkinsonism types” and remind that multiple etiologies are possible to explain the patient‟s neurologic syndrome (Weiner 2008). In the future, PD will be probably subdivided into different varieties and ethiologies, maybe assigning numbers to each different “parkinsonism types”. Figure 17: Pathologic mechanisms in the etiology of PD
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INTRODUCTION
Misfolding and aggregation of proteins Dysfunction at any stages of protein production (transcription and translation, post-translational modification, trafficking and degradation) can lead to malformed proteins and aggregation. There is now compelling evidence that protein aggregation and abnormal processing of proteins are involved in the pathogenesis of PD (Schulz and Dichgans 1999). Despite the rarity of the familial forms of PD, the identification of single genes linked to this disease has provided decisive insights into probable mechanisms of its pathogenesis. Mutations in the genes α-synuclein, parkin or UCH-L1 are thought to impair the protein degradation pathway involving ubiquitination and the proteasome (Figure 18B). The protein α-synuclein is the major constituent of the LB. In its native state, monomeric α-synuclein is a soluble unfolded protein that under certain conditions is prone to misfold and to aggregate forming oligomeric species. These oligomers, termed protofibrils, are soluble and can then become amyloid-like fibrils which are insoluble. These latter are the major components of LB (Spillantini et al. 1998) and can also form LN in neuronal processes. Mutations on SNCA, the gene encoding α-synuclein, cause a rare autosomant dominant form of familial PD (Polymeropoulos et al. 1997, Kruger et al. 1998). Genomic rearrangement in the form of duplication and triplication of the wild type (wt) SNCA gene cause typical and atypical PD, respectively (Singletton et al. 2003, Chartier-Halin et al. 2004, Ibañez et al. 2004, Fuchs et al. 2007) and the presence of increased copy numbers of the wt α-synuclein gene causes PD (Ibañez et al. 2004). Moreover, α-synuclein aggregates are also found in various other neurodegenerative diseases termed synucleinopathies, such as MSA, DLB, and pure autonomic failure (Trojanowski and Lee 2002).
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INTRODUCTION
Figure 18: The ubiquitin-proteasome system (A) and possible sites where different forms of PD might interfere with the UPS (B) (Olanow and McNaught 2006)
The discovery of ubiquitin as a major constituent of LB (Kuzuhara et al. 1988) was the first evidence that suggest the involvement of the ubiquitin-proteasome system (UPS) dysfunction in the pathogenesis of PD. This was later supported by the identification of parkin mutations associated with young onset autosomal recessive PD (Kitada at al. 1988). The UPS is the major mechanism used to degrade abnormal proteins, or proteins at the ends of their life cycles. Misfolded or unwanted proteins targeted for degradation are covalently modified via polyubiquitination on lysine residues and directed to the proteasome. Three enzymes are required: ubiquitinactivating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases 34
INTRODUCTION
(E3) (Figure 18A). Loss-of-function mutations in parkin, an E3 ubiquitin ligase, abolish its activity leading to proteasomal dysfunction and subsequent accumulation of aggregated proteins (Cookson 2005, Yang et al. 2009). Parkin was also shown to interact with PINK1 (PARK6 gene) and DJ-1 (PARK7 gene) (Shiba et al. 2009, Um et al. 2009). These three PD-related proteins physically interact and form a functional E3 ligase complex to regulate UPS-mediated protein degradation (Xiong et al. 2009). The role of the UPS in neurodegeneration was also enhanced with the identification of mutation I93M in UCH-L1 (Leroy et al. 1998) in autosomal recessive PD. The UCH-L1 protein is a de-ubiquitinating enzyme, it cleaves ubiquitin from the ubiquitin-protein adduct enhabling the protein to enter the proteasome. UCH-L1 mutations may prejudice proteasomal degradation and also lower the availability of ubiquitin monomers required for the removal of additional misfolded proteins. Some studies demonstrated another mutation within this gene (S18Y) that decreases risk for PD, but this remains controversial (Maraganore et al. 2004, Healy et al. 2006). In brief, when a component of the UPS required for degrading proteins is altered or the capacity of UPS has been exceeded as an outcome of the excessive production of misfolded proteins, or a combination of both, proteolytic stress happens (Figure 18B, Olanow 2007). This leads to the accumulation and aggregation of proteins with subsequent damage in a wide range of cellular functions and apoptosis.
35
INTRODUCTION
Mitochondrial dysfunction Many data support now a role for aberrant mitochondrial form and function in the pathogenesis of PD (Schapira 2008). Mitochondria are essential for the generation of cellular energy through oxidative phosphorylation. They are also the major cellular source of free radicals and are implicated in the regulation and initiation of cell death pathways and in calcium homeostasis. Mitochondria dysfunction can lead to insufficient ATP production hence impairing all ATP-dependent cellular processes and generate and accumulate ROS, rendering then cells more vulnerable to oxidative stress and other interconnected processes, including excitotoxicity. Originally, MPTP toxicity and reduction of complex I activity in the SNpc of PD patients provided evidence for the participation of mitochondrial pathways in PD (Schapira et al. 1992, Mann et al. 1994). Moreover, demonstration of the involvement of PD-associated genes products in mitochondrial function reinforced the connection between PD and mitochondrial biology (Dodson and Guo 2007). Mutations of these PD-associated genes will likely disrupt mitochondrial function and affect the cellular response to oxidative stress. PINK1, a mitochondrial serine-threonine kinase that shares homology with calmodulin
(CaM)-dependent
protein
kinase
I,
localizes
principally
within
mitochondria, in particular at the outer mitochondrial membrane (Zhou et al. 2008) while others suggested an inner mitochondrial membrane localization (Silvestri et al. 2005, Gandhi et al. 2006) or a cytoplasmic pool (Weihofen et al. 2007, Haque et al. 2008). PINK1 seems to provide protection against oxidative stress (Valente et al. 2004, Yang et al. 2006). Its overexpression defends cell from mitochondrially-induced apoptosis caused by staurosporine, and from mitochondrial depolarization and apoptosis generated by the proteasomal inhibitor MG132 (Wood-Kaczmar et al. 2008). PINK1 is thought to interact with HTRA2 (Plun-Favreau et al. 2007), a mitochondrial serine protease, that is released from the mitochondrial intermembrane space into the cytosol, where it induces apoptotic cell death in addition to the permeabilization of the mitochondrial membrane leading to cytochrome c release (Suzuki et al. 2001, Hegde et al. 2002, Suzuki et al. 2004). Furthermore, recent studies suggest that PINK1 could act
36
INTRODUCTION
in connection with Parkin, maybe controlling the balance between mitochondrial fission and fusion (Deng et al. 2008), and also with α-synuclein (Marongui et al. 2009). Parkin is located partially to the outer mitochondrial membrane (Darios et al. 2003) and also in the mitochondrial matrix. Parkin protects against oxidative stress and has a hypothesized role in mitochondrial gene transcription and biogenesis in proliferating cells, but the precise mechanism is unknown (Jiang et al. 2004). A recent study demonstrated a primary function for Parkin in the regulation of mitochondrial turnover. Actually, Parkin was shown to be specifically recruited to damaged or uncoupled mitochondria with low potential membrane to promote their clearance through the autophagosome (Narendra et al. 2008). Another PD and mitochondrial function related protein is DJ-1, which is mainly expressed in the cytosol, in the nucleus and in the mitochondria (a pool located in the mitochondrial intermembrane space and in the matrix). DJ-1 is thought to be neuroprotective (Abou-Sleiman et al. 2003, Zhang et al. 2005, Abeliovich and Flint Beal 2006, Zhou et al. 2006, Andres-Mateos et al. 2007, Schapira 2008) as it was recently reported to translocate to the mitochondria under conditions of oxidative stress (Junn et al. 2008). DJ-1 is then relocalized into the nucleus, where it is proposed to bind multiple RNAs and regulate p53‟s transcriptional activity.
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INTRODUCTION
Oxidative stress Oxygen is necessary for life, but paradoxically, it is also toxic as a by-product of its metabolism produces ROS (Reaction 1). ROS are defined as molecular entities that react with cellular components, resulting in detrimental effects on their function as they are highly toxic to cells. ROS include both molecular species, such as hydrogen peroxide (H2O2), and free radicals (a term used to designate any chemical species containing highly reactive unpaired electrons), such as superoxide anion (O2●─), and hydroxyl radical (●OH). The latter is the most potentially dangerous of ROS, short-lived but highly reactive, which causes enormous damage to biological molecules. In addition to ROS, reactive nitrogen species (RNS) are also generated notably nitric oxide (NO●, NO) and peroxynitrite (ONOO●─). Reaction 1: ─
O2 + e → O2
Metabolism of O2 and production of ROS ●─
─
─
●
─
─
+ e + 2H+ → H2O2 + e → OH + OH + e + 2H+ → 2H2O
ROS can interact with nearby critical cellular components such as membrane lipids, proteins, and DNA and oxidize them, leading to a wide range of damaging effects. In the case of proteins, ROS may directly oxidize amino acids leading to loss of functions of proteins and disruption of the active sites of enzymes. Exposure of membranes of fatty acids to ROS may result in the formation of alkoxyl (RO●), peroxyl (ROO●), and lipid epoxides and hydroperoxides (ROOH). The latter can additionally be further oxidized close by unsaturated fatty acids in a chain reaction event stimulated by ROO● and RO●, leading to disruption of both plasma and mitochondrial membranes. Oxidation of nucleic acids may provoke strand breakage, nucleic acid-protein crosslinking, and nucleic base modifications which can have an effect on DNA transcription, translation and replication. Within neurons ROS may also interfere with signal transduction and gene expression affecting cell survival, thus inducing cell death.
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INTRODUCTION
Oxidative damage happens in all our tissues all the time. There is a basal level of oxidative damage to DNA, lipids and proteins (Halliwell and Gutteridge 2006) and under normal conditions free radicals will be quickly detoxified by the body‟s defence systems. Mechanisms that resist against oxidative damage comprise antioxidant scavengers such as glutathione (GSH), ascorbic acid (AA), alfa-tocopherol, carotenoids, flavonoids, polyphenols and antioxidant enzymes. These latter, SOD, GPx, CAT, are known to be responsible for the detoxification of ROS: SOD catalysing the dismutation of two molecules of O2● to give H2O2 and O2, and GPx and CAT participating in the removal of H2O2 (Reactions 2 and 3). Nevertheless, under certain circumstances, greater amounts of ROS and RNS are produced, which finish up by overcoming the cellular defence mechanisms. Failures in the systems that repair and replace oxidized biomolecules contribute to a situation of oxidative stress, defined as “an imbalance between oxidants and antioxidants, in favour of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage” (Sies and Jones 2007). Reaction 2: ●─
2 O2
Dismutation of O2 by SOD SOD
+ 2H+
Reaction 3:
H2O2 + O2
Removal of H2O2 by GPx GPx
2 GSH + H2O2
GSSG + 2H2O
In the past decades, oxidative stress was the first common pathogenic factor to be considered as contributing to the degeneration of DAergic neurons in PD (Jenner 1998, Lang and Lozano 1998, Schapira 1999). Increased SOD, iron, lipid peroxidation markers and nitrated proteins levels, and decreased GSH levels in SNpc of PD patients suggested that oxidative stress may play a significant function in PD neurodegeneration (Saggu et al. 1989, Sofic et al. 1991, Sofic et al. 1992, Ilic et al. 1999, Agil et al. 2006).
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INTRODUCTION
Transition metals: the example of iron Iron is a redox-active metal able to generate O2●─ from its interaction with molecular oxygen by auto-oxidating (Reaction 4). The reverse reaction is also possible. As a result of the Fenton reaction (Reaction 5), Fe2+ may also be oxidized in the presence of H2O2 and generate ●OH and Fe3+ which provokes lipid oxidation through its reaction with hydroperoxides normally present in the biological systems. In biological environment, other reactions as the Haber-Weiss reaction also occurs and requires the catalytic contribution of redox metal ions (Reaction 7).
Reaction 4 Reaction 5 Reaction 6 Reaction 7
●─
Fe2+ + O2 → Fe3+ + O2 ●─ 2 O2 + 4H+ → 2H2O2 ● ─ Fe2+ + H2O2 → Fe3+ + OH + OH ●─ 3+ 2+ Fe + O2 → Fe + O2 ●─ ● ─ O2 + H2O2 → O2 + OH + OH
(Fenton reaction) (Haber Weiss reaction)
In PD, iron content of the SNpc is elevated with an increase of the Fe3+/Fe2+ ratio from 2:1 to almost 1:2 (Riederer et al. 1988, 1989, Sofic et al. 1988, Dexter et al. 1993). These levels of iron increase the conversion of H2O2 to ●OH via the Fenton reaction and promote a greater turnover in the Haber-Weiss reaction, leading to an amplification of oxidative stress (Riederer and Youdim 1993). Alternatively, oxidative stress may increase the levels of free iron (Halliwell and Gutteridge 2003) which may interact with α-synuclein promoting its aggregation (Schipper et al. 1998, Hochstrasser et al. 2004).
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INTRODUCTION
DA metabolism as a source of ROS The selective neurodegeneration of SNpc DAergic in PD seems to suggest that these neurons are more vulnerable to oxidative stress, but the reason behind this is not completely understood. One potential explaination was based, at least in part, on DA metabolism either by autoxidation or catalyzed by MAO. Actually, this neurotransmitter can react with molecular oxygen generating peroxides, active quinones, OH and other ROS that, along with those created from the respiratory chain failure, may lead to both modifications of proteins and depletion of GSH generating a highly oxidative intracellular environment. The MAO catalyzed oxidation of DA to 3,4-dihydroxyphenylacetaldehyde (DOPAL) leads to H2O2 formation, which is normally cleared by GSH. As GSH levels are decreased in SN of PD patients (Sian et al. 1994) H2O2 may be converted into OH which may trigger lipid peroxidation causing the death of DAergic neurons. Furthermore, DA autoxidation results in the formation of the semiquinone radical which can be directly toxic (Stokes et al. 1999, Danielson and Andersen 2008) or which can lead to the formation of ROS (Olanow 1990). O2●─ is either metabolized into H2O2 or reacts with NO, generating the strongly reactive ONOO●─. After a complex process of polymerization, this autoxidation pathway leads finally to the generation of the darkcoloured, insoluble pigment called neuromelanin (Graham 1978). This compound was implicated
in
the
vulnerability
and
susceptibility
of
DAergic
neurons
to
neurodegeneration (Abou-Sleiman et al. 2006) but its precise mechanism remains uncertain. Several hypotheses tried to explain its contribution to the DAergic neurons death, through a macromolecule crowding effect or as an intraneuronal toxic reservoir by binding transition metals like iron or neurotoxic coumpounds like MPP+ (Chung et al. 2001).
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INTRODUCTION
Nitric oxide There is evidence that not only ROS but also the metabolism of NO, a free radical, may play a part in oxidative damage in PD (Gerlach et al. 1999, Torreilles et al. 1999, Boje 2004). NO is synthesized from L-arginine by three isoforms of nitric oxide synthase (NOS): inducible (iNOS), endothelial (eNOS), and neuronal NOS (nNOS), using NADPH and molecular oxygen (Kavya et al. 2006). NO has long been recognized as a signaling molecule for vasodilatation and neurotransmission but it has many important functions in other physiologic systems, such as in the immune, respiratory, neuromuscular and nervous systems. Moreover, NO also participates in pathogenic pathways. It can react with other ROS to generate the highly toxic RNS (Reynolds et al. 2007, Szabo et al. 2007). As depicted in Figure 19 NO can react with O2●─ to form the more reactive ONOO●─. Peroxynitrite is known to promote cellular damages by means of lipid peroxidation, DNA fragmentation, protein nitration, and activation of caspase dependent and/or independent cell death pathways (Beckman and Koppenol 1996, Hong et al. 2004, Szabo et al. 2007). Additionnally, when reacted with H+ or CO2, ONOO●─ can further convert to nitrogen dioxide (NO2) and ●OH, two highly toxic intermediates. Protein modifications by NO and/or ONOO●─ such as S-nitrosylation and nitration may affect cell survival. Protein nitration by NO or ONOO●─ usually inserts a nitro (-NO2) group onto one of the two carbons of the aromatic ring of tyrosine residues to form nitrotyrosine (Gow et al. 2004). On the other hand S-nitrosylation, which also happens under both physiologic and pathogenic conditions, regulates gene transcription, vesicular trafficking, receptor mediated signal transduction, and apoptosis (Chung 2007). Many enzymes, receptors and neuroprotective proteins may be modified by NO through their reactive cysteine (CySH) thiols to form the corresponding nitrosothiols (Stamler et al. 1992, Ahern et al. 2002, Hess et al. 2005, Chung 2007).
42
INTRODUCTION
Contribution of oxidative and nitrosative stress to PD pathogenesis As we have previously seen, genes linked to familial PD are important in mitochondrial function or in the handling of misfolded proteins (Abou-Sleiman et al. 2006, Savitt et al. 2006, Sulzer 2007). Besides, oxidative and nitrosative stress had a significant effect on the normal function of familial PD-related gene products in the process of neurodegeneration. Figure 19: Generation of ROS and RNS in SNpc neuron (Tsang and Chung 2009)
Oxidative stress is known to promote protein misfolding and aggregation. For example, α-synuclein can undergo oxidative modifications such as the addition of a DA adduct on α-synuclein (Conway et al. 2001). This modification stabilizes the toxic αsynuclein protofibrils and makes it resistant to chaperone mediated autophagy (CMA) leading to a complete blockade of other proteins degradation via this pathwaw (Martinez-Vicente et al. 2008). As well, α-synuclein protofibrils can permeabilize synaptic vesicles (Volles et al. 2001, Mazzulli et al. 2006, Mosharov et al. 2006) leading to an increase of more α-synuclein protofibrils. Nitrosative modifications of α-synuclein
43
INTRODUCTION
have also been demonstrated in all tyrosine residues (Takahashi et al. 2002). Nitrated αsynuclein is more prone to aggregation (Giasson et al. 2000, Zhang et al. 2000), more resistant to proteolysis and more immunogenic explaining why inflammatory responses are frequent in PD patients (Goedert 2001, Benner et al. 2008). We have previously also commented that PINK-1 and DJ-1 are known to possess protective function against oxidative stress (Savitt et al. 2006, Thomas and Beal 2007). Oxidative and nitrosative stress can also impair cellular systems that protect against misfolded or aggregated proteins. As an example, parkin can be S-nitrosylated on a critical CySH residue within its catalytic RING domains impairing its E3 ligase activity and neuroprotective functions (Chung et al. 2004, Yao et al. 2004). Additionally, DA can covalently modify parkin leading to parkin aggregation and weakening its ligase activity (LaVoie et al. 2005). S-nitrosylated and DA-modified parkin were observed in the SNpc of PD patients. Moreover, normal UPS function can also be compromised by the tendency of oxidized proteins to be more resistant to proteasomal degradation probably by means of the formation of aggregates (Friguet and Szweda 1997, Davies 2001). Protein aggregates may also lead to the UPS impairment by blocking the access of the proteasome to other proteins (Grune et al. 2004). Despite being the major site of ROS formation, the respiratory chain itself is targeted by oxidative stress. Complex I and various enzymes in the Krebs cycle can be inactived by oxidation (Cadenas and Davies 2000, Cecarini et al. 2007) contributing to the reduction of the ATP biosynthesis. Moreover, mitochondrial DNA (mtDNA) that is transitorily connected to the inner mitochondrial membrane is particularly vulnerable to oxidative damage (Goetz and Gerlach 2004). Consequently ROS-induced mtDNA injury may play a part in mitochondrial dysfunction (Stewart and Heales 2003).
44
INTRODUCTION
Excitotoxicity Glutamate is the major excitatory neurotransmitter in the CNS, but it can be toxic to cells. Excitotoxicity is a pathological process that may occur as a consequence of an excessive stimulation of the glutamate N-methyl-D-aspartate receptor (NMDAR) and other receptors associated with glutamatergic signalling, such as metabotropic glutamate receptors (mGLURs), calcium channels and other G-protein coupled receptors (GPCR), and the subsequent massive influx of extracellular calcium. This toxic and pathological increase in cytoplasmic calcium activates a number of calciumdependent enzymes involved in the catabolism of proteins, phospholipids and nucleic acids, and in the synthesis of NO leading in turn to mitochondrial damage, formation of oxidizing species, and downstream activation of cell death pathways. There is some evidence implicating excitotoxicity as one contributing mechanism to the pathogenesis in PD. As the SN receives rich glutamatergic inputs from neocortex and the STN, the demise of nigrostriatal DA in PD leads to disinhibition of striatal neurons, and consequently to disruption of the neurotransmitter balance in striatum resulting in glutamatergic overactivity, whereas under physiological conditions there is equilibrium between the activation of striatal neurons through NMDAR and inhibition by the D2 receptors. It was hypothesized that weak excitotoxicity may happen secondary to a mitochondrial defect with decreased ATP formation leading to an ATP dependent magnesium-blockade of the NMDAR or to disinhibition of glutamatergic STN neurons resulting from DA depletion (Beal 1998, Rodriguez et al. 1998). Furthermore, NMDAR antagonists were shown to provide protection against MPP+induced neurotoxicity and obtain antiparkinsonian like activity in animal models (Turski et al. 1991, Uitti et al. 1996, Schmidt and Kretschmer 1997) whereas compounds that enhance NMDAR function worsens parkinsonian symptoms (Giuffra et al. 1993). In addition, NO has been associated with NMDAR excitotoxicity. During over-activation of the NDMAR, nNOS is recruited to the glutamate receptor by a postsynaptic density protein called PSD-95 and synthesizes then NO which can react with other ROS to form the highly toxic ONOO●─ (Sattler et al. 1999, Aarts et al. 2002).
45
INTRODUCTION
Another pathway has been linked to excitotoxicity. In PD there is evidence for abnormal activation of cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase which needs activating partners, p35 and p39 (Cheung et al. 2004, Cheung 2006). Overactivation of NMDAR was shown to provoke cleavage of p35 to p25, a protein that cause a more robust and prolonged activation of Cdk5. Excessive Cdk5 activity has been linked to PD pathogenesis (O‟Hare et al. 2005, Smith et al. 2006, Wang et al. 2007, Qu et al. 2007) and is known to contribute to neuronal death by phosphorylating the transcription factor myocyte enhancer factor 2 (MEF2) and the antioxidative stress enzyme peroxiredoxin 2 (Prx2), leading to attenuation of their normal prosurvival functions. Actually, Prx2 breaks down H2O2 to H2O and O2 protecting the cells against oxidative stress (Abou-Sleiman et al. 2006), whereas MEF2 is an important transcription factor of prosurvival genes (Potthoff and Olson 2007).
Neuroinflammation and glial cells It is well known that the brain can initiate injury responses, such as neuroinflammation, as a way to clean up injured brain tissues. The main cellular responders are microglia, specialized macrophages capable of producing cytokines and other protective factors to regulate the injury response. Although neuroinflammation may have initial protective effects, it has been hypothesized to be a potential contributor to PD pathogenesis (Hartmann et al. 2003). Its exact role is unclear: it may act as an initial event of PD pathogenesis or be a downstream result of another triggering pathogenic factor. Immunohistochemical studies have demonstrated the presence of activated microglia, increased expression of iNOS, cytokines like tumour necrosis factor-α (TNFα) and interleukin (IL)-1β, and pro-inflammatory signalling cascades such as cyclooxygenase-2 (COX-2) and NF-κB in striatum, SN and cerebrospinal fluid (CSF) of PD patients (Boka et al. 1994, Mogi et al. 1994, Blum-Degen et al. 1995, Hunot et al. 1996, Hirsh et al. 1998, Muller et al. 1998, Hunot et al. 1999, Knott et al. 2000, Nagatsu et al. 2000, Nagatsu 2002). Animal models of PD using rotenone, MPTP, and 6-OHDA showed levels of microglial activation similar to what is found in PD (Czlonkowska et 46
INTRODUCTION
al. 1996, Cicchetti et al. 2002, Sherer et al. 2003). In post-mortem examination of brains from humans exposed to MPTP, activated microglia was present up to 16 years after exposure indicating a long-lasting and ongoing inflammatory response (Langston et al. 1999). Indeed, the inflammatory cytokines seem to intensify and perpetuate the neuroinflammation (McGeer et al. 2001, Orr et al. 2002, McGeer and McGeer 2004, Bartels and Leenders 2007). Furthermore, neuromelanin, which is released by dying DAergic neurons, was shown to activate microglia in vitro (Wilms et al. 2003). As large amounts of superoxide radicals are produced by activated microglia, chronic neuroinflammation may then promote the degeneration of DAergic neurons once activated, probably through increased oxidative stress (Figure 20; Whitton 2007). This may lead to the creation of a vicious cycle that further increases DAergic toxicity in the SNpc. Figure 20: Interaction between microglia and DAergic neurons (Whitton 2007)
47
INTRODUCTION
Cell death pathways There is substantial indication that cell death in PD occurs by way of a signalmediated apoptotic process (Hirsch et al. 1999, Mattson et al. 2000). Apoptosis is a mechanism of programmed cell death (PCD) carried out by caspases during which a cell goes through various morphological changes including membrane blebbing, changes to the cell membrane such as loss of membrane asymmetry and attachment, cell shrinkage, nuclear condensation, and DNA fragmentation. A normal functioning of apoptosis avoids triggering harmful responses, such as inflammation. A great number of apoptotic pathways are activated in response to PD-induced dysfunction, such as JNK signaling, induction of Bax, p53 activation, cell cycle re-entry, bcl-2 family signalling, and caspase activation (Hirsch et al. 1999, Tatton et al. 2003, Nair et al. 2006, Levy et al. 2009). As an example, mutations in LRRK2 are linked to activation of the intrinsic apoptotic pathway, with cytochrome c released into the cytosol, activation of caspase 3 and nuclear condensation (Iaccarino et al. 2007).
48
INTRODUCTION
Experimental models of PD Animal models are invaluable tools to understand the pathophysiology and motor deficits occurring in PD disease. Furthermore, they are also fundamental to create new neuroprotective strategies and therapeutic interventions to improve symptomatic management. Since PD does not develop spontaneously in animals, various models have been developed in distinct species in order to mimic the characteristic functional changes observed in PD. These include toxin-based models, gene-based models and inflammation-based models.
Toxin-induced models 6-OHDA, the first animal toxin-based model of PD associated with loss of DAergic neurons in the SNpc was introduced more than 40 years ago (Ungerstedt 1968). Since then many different neurotoxins, such as MPTP, paraquat and rotenone have been used to induce DAergic neurodegeneration in animal models.
6-OHDA The discovery of 6-OHDA toxicity toward catecholaminergic neurons initiated the epoch of toxin-based models of PD (Ungerstedt 1968, Ungerstedt and Arbuthnott 1970). As 6-OHDA does not cross the BBB it must be administered directly in the brain by local stereotaxic injection into the SN, median forebrain bundle (MFB), or striatum, with the contralateral side serving as control, or by peripheral administration in neonatal rats (Perese et al. 1989, Przedborski et al. 1995, Rodriguez-Pallares et al. 2007, Sánchez-Iglesias et al. 2007a). 6-OHDA injection into the striatum leads to a more progressive and slower degeneration of nigrostriatal neurons, which lasts for 1-3 weeks (Sauer and Oertel 1994, Przedborski et al. 1995, Fleming et al. 2005), while injections into SN or the nigrostriatal tract result in striatal DA depletion 2 to 3 days later (Faull and Laverty 1969). The quantity of neurotoxin used, the site of injection, and the different sensitivity between animal species determines the extent of the lesion.
49
INTRODUCTION
Although the 6-OHDA model does not replicate many features of PD, such as extranigral pathology or LB-like inclusions (Dauer and Przedbroski 2003, Lane and Dunnett 2008), it is still extensively used. This model is particularly useful to quantitatively assay the anti-PD properties of compounds for pharmacological screening. Other 6-OHDA models, like bilateral intrastriatal (Roedter et al. 2001) or intraventricular administration of 6-OHDA (Rodriguez et al. 2001, Rodríguez-Díaz et al. 2001, Rey et al. 2007, Sánchez-Iglesias et al. 2009), were successfully developed with methods meant to cause a bilateral and more slowly arising PD.
MPTP MPTP is one of the most common toxins used to mimic the hallmarks of PD. Its metabolite MPP+ is a potent complex I inhibitor in DAergic neurons and an excellent substrate for DAT, a fact that explains its selectivity towards DAergic neurons. Acute, subacute and chronic MPTP protocols are generally used with some variations in mice (Lau et al. 1990, Rozas et al. 1998, Petroske et al 2001, Muñoz et al. 2006, Joglar et al. 2009) as rats are not susceptible to MPTP. Loss of DAergic neurons, bradykinesia, rigidity, and posture abnormalities developed in systemic MPTP treatment (Sedelis et al. 2000). As well, small granular inclusions containing -synuclein were seen in SN DAergic neurons, so as an extra-nigral pathology (Wallace et al. 1984, Hallman et al. 1985, Meredith et al. 2002, 2004). Recently, a technically challenging intraventricular MPP+ chronic rat model has also been developed (Yazdani et al. 2006)
Rotenone, paraquat and maneb Rotenone, a natural cytotoxic coumpound widely used as pesticide, is highly lipophilic and can easily cross cell membranes and the BBB. Chronic exposure of rotenone potently and uniformly inhibits mitochondrial complex I binding at the same site as MPP+ throughout the rat brain. The herbicide 1,1‟-dimethyl-4,4‟-bipyridinium or paraquat (PQ) can also crosses the BBB and shares structural similarity to MPP+ but has no selectivity for DAT. PQ is reduced by complex I leading to formation of a PQ radical capable of disrupting mitochondrial function. Treatments with rotenone and paraquat 50
INTRODUCTION
induce selective DAergic neuron degeneration and have been used to model sporadic Parkinson's disease (Brooks et al. 1999, Peng et al. 2004, Hsuan et al. 2006, Inden et al. 2007). Animal models using paraquat generally also co-administer maneb (manganese ethylenebisadithiocarbamate) to enhance toxicity. Nevertheless, general toxicity of PQ and rotenone make their use difficult. As MPTP they produce nigrostriatal degeneration but their effects are more widespread. A recent study suggested that rotenone and paraquat do not induce neuroinflammation and microglial activation directly but rather indirectly as a result of DAergic neuron damage or through factors released by neurons or astrocytes (Klintworth et al. 2009).
Inflammation-based models Neuroinflammation is present in PD and is believed to contribute to PD pathogenesis.
Therefore,
inflammation-based
models
have
been
developed.
Lipopolysaccharide (LPS) is a bacterial coat protein and has been used to model neuroinflammation in PD as it is a potent activator of microglial cells and inducer of inflammation (Whitton 2007). Distinct protocols have been used by the date: acute intracerebral (Castano et al. 1998, Herrera et al. 2000, Kim et al. 2000, Iravani et al. 2005), chronic intracerebral (Gao et al. 2002), acute systemic (Quin et al. 2007), and intrauterine (Ling et al. 2002, 2004, 2006) administration of LPS. LPS causes DAergic cell death and decreases locomotor activity in rodents (Iravani et al. 2005).
Gene-based models More recently, the identification of genetic mutations of PD has enabled the creation of etiologic-specific PD animal models. These include genetically modified mice with null mutations of parkin, DJ-1 and PINK1 genes (knock-out mice), an extra gene copy of -synuclein and LRRK2, or point mutations of genes located in different PARK loci (Goldberg et al. 2003, Itier et al. 2003, Palacino et al. 2004, Von Coelln et al. 2004, Smith et al. 2006, Chesselet 2007, Dodson and Guo 2007, Kitada et al. 2007, Sang et al. 2007, Yamaguchi et al. 2007, Yang et al. 2007, Zhu et al. 2007). Additional
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INTRODUCTION
mouse models, such as Pitx3-aphakia mouse or Engrailed double knock-out mouse, were developed on the basis of genes crucial for development and survival of DAergic neurons (Nunes et al. 2003, Sgado et al. 2006, Ding et al. 2007). Recently, tissuespecific knock-out mouse models targeting the expression of genes of interest in a region- or neuron-specific manner were created (Gelman et al. 2003, Ekstrand et al. 2004, Lindeberg et al. 2004, Backet et al. 2005, Zhuang et al. 2005, Backman et al. 2006, Borgkvist et al. 2006, Turiault et al. 2007). As there is no experimental PD model to date that mimics exactly the pathogenesis and progression happening in PD, one priority at this time is to develop an experimental model of PD that reproduces the clinical and pathological features of PD, such as progressive loss of DAergic neurons in the striatum and SN, LB-like inclusion in the brain, and L-DOPA-responsive movement disorder.
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INTRODUCTION
ALUMINIUM
General features The human organism is constantly and inevitably exposed to aluminium, a ubiquitous metal which is the third most abundant element in the Earth‟s crust (after oxygen and silicon), representing 8.3% of total components (Becaria et al. 2002). Its atomic number is 13 and its electronic configuration is [Ne]3s23p1. Aluminium has two isotopes, Al27 which has a natural abundance of 99.9% and Al26 with a half-life (t1/2) of 7.2 105 years. In nature, aluminium does not occur in the elemental state but is found in combination with oxygen, fluorine, silicon, sulphur and other species (Brusewitz 1984, Wagner 1999). The physical, chemical and biological properties of the aluminium complexes will determine the toxicokinetics of this metal (Harris et al. 1997).
Aluminium speciation Aluminium forms a wide range of hydroxyl complexes in water solution, evolving from Al3+ towards [Al(OH)4]- within the 3-8 pH range (Reaction 8; Figure 21). Reaction 8: [Al(H2O)6]3+ [Al(H2O)5(OH)]2+ [Al(H2O)4(OH)2]+ Al(OH)3 [Al(OH)4]-
Actually, in aqueous solution at pH < 5.0, the prevalent mononuclear Al species is the octahedral hexahydrate [Al(H2O)6]3+ (generally abbreviated as Al3+). In less acidic solutions with pH values greater than 5.0, [Al(H2O)6]3+ undergoes hydrolysis that yield different species such as [Al(H2O)5(OH)]2+ (abbreviated as [Al(OH)]2+) and [Al(H2O)4(OH)2]+ (abbreviated as [Al(OH)2]+). But not only mononuclear aluminium species exist in aqueous solution, as it is inclined to polymerize forming the unstable dimer [Al2(OH)2(H2O)8]4+ and the more stable polymers [Al6(OH)12]6+, [Al10(OH)22]8+
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INTRODUCTION
and [Al13(OH)30]9+. The solid Al(OH)3 is the predominant species in the neutral pH range, whereas the soluble tetrahedral aluminate [Al(OH)4]- predominates above pH 8. Figure 21: Mole fraction of soluble aluminium ions as a function of solution pH in aqueous solution (Priest 2004)
Sources of aluminium exposure Environmental exposure Aluminium and its compounds are widely distributed in the environment although most naturally occurring aluminium is bound and not readily bioavailable. As example, this metal is present in a variety of minerals, such as silicates (feldspars and micas), complexed with fluorine and sodium as cryolite, and is chiefly mined as bauxite, a mineral containing 40-60% aluminium oxide (alumina) (Ganrot 1986). Aluminium is a major constituent of atmospheric particulates, primarily found as alumino-silicates, originating from natural soil erosion, mining or agricultural activities, volcanic eruptions, or coal combustion. Atmospheric aluminium concentrations were reported to range generally from 5 to 180 µg/m3 (Sorenson et al. 1974) whereas concentrations in industrial areas are often in the milligram per cubic meter range.
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INTRODUCTION
Varying amounts of aluminium are present naturally in groundwater and surface water, including those used as sources of drinking water. Acidification of lakes and streams by acid rain mobilize aluminium from the soil to the aquatic environment increasing the amount of this metal (Cronan and Schoefield 1979, Harris et al. 1996). Aluminium concentrations in natural water normally are small but may vary in the urban areas (Constantini and Giordano 1991) depending if aluminium flocculents (most commonly alum or aluminium sulphate) are used during the treatment process for purification purposes for clarifying turbid drinking water (Martin 1986, Lévesque et al. 2000).
Dietary exposure Aluminium is found in the tissues of many plants and animals. The concentration in foods varies widely, depending upon the product, the type of processing, and the geographical origin (means range from <0.001 to 69.5 mg/100 g; Pennington 1988). The main source of aluminium intake is food, where the major contributors are probably products containing aluminium as food additives (grain products, processed cheese, and baked goods), and also tea, herbs, spices, and soy-based milk products. The total consumption of Al in a normal diet was estimated to range from 1 to 20 mg/day (Sorenson et al. 1974, Alfrey 1983), whereas higher levels (3-100 mg) were also reported (Lione 1983). A more recent study estimated mean aluminium intake as 10 and 7 mg/day by an adult male and female, respectively (Flarend et al. 2001). Aluminium leaching from cookwares, beverage cans, and packaging made of aluminium also may contribute to dietary exposure (Lione 1984, Greger et al. 1985, Regura et al. 1985, Kandiah and Kies 1994, Lin et al. 1997).
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INTRODUCTION
Iatrogenic exposure In short, the major route of aluminium exposure for an adult is food (approximately 95%), drinking water only contributes <5%, whereas the contribution from ambient air is generally negligible. However, this average may be greatly increased as high as 5 g/day in individuals who regularly consume high doses of nonprescription aluminium-containing drugs, such as antacids, buffered analgesics, antidiarroheal products, and hemorroidal medications (Lione 1985, Graves et al. 1990, Flaten et al. 1991, Nieboer et al. 1995, WHO 1997, Flaten et al. 2001). Moreover, aluminium-containing adjuvants in the commonly used vaccines (diphtheria, tetanus, hepatitis, rabies, and anthrax), phosphate binders, dialysis, total parenteral nutrition (TPN) solutions are frequent and can also result in a significant increase in aluminium exposure (Yokel and McNamara 2001).
Other types of acute aluminium intoxication are unusual in clinical practice but have been found to happen. Patients undergoing cranial bone reconstruction with aluminium-containing bone cement (Hantson et al. 1994) or after reconstructive otoneurosurgery (Reusche et al. 2001), receiving alum irrigation in the urinary bladder to prevent bleeding (Kavoussi et al. 1986, Murphy et al. 1992), with severe burns (Klein et al. 1994), on TPN (Klein et al. 1982, Klein and Coburn 1994), and preterm infants on intravenous feed (Sedman et al. 1985, Bishop et al. 1989) were found to be victims of aluminium exposure.
Occupational exposure There is also potential for occupational exposure to aluminium due to processing of the metal in industries (Sjögren et al. 1997, Meyer-Baron et al. 2007). Cognitive changes and possible impairment were reported before in relation to exposure to aluminium dusts and fumes (Hosovski et al. 1990, Rifat et al. 1990, White et al. 1992, Bast-Pattersen et al. 1994, McLachlan 1995). In addition, aluminium-containing compounds such as preservatives, coloring agents, leavening agents (Soni et al. 2001),
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INTRODUCTION
and antiperspirants containing aluminium chlorohydrate (Flarend et al. 2001) represent other possible sources of exposure.
Aluminium toxicokinetics Absorption of aluminium Aluminium may be absorbed by several routes: oral, intranasal, transdermal, and parenteral pathways. The major sites of aluminium absorption are the gastrointestinal tract (Ittel 1993), the skin (Exley 1998, 2004), and the olfactory and oral epithelia (Roberts 1986).
Oral absorption The gastrointestinal tract is one of the main sites of aluminium absorption (Ittel 1993). The proportion of absorbed aluminium following oral intake is very low ranging from 0.06 to 1.5% (Moore et al. 2000, Flaten et al. 2001, Yokel et al. 2001a). The amount of aluminium absorbed across the gastrointestinal tract depends on many factors, including pH, aluminium speciation and dietary agents (Partridge et al. 1989, Deng et al. 1998). Moreover, the intestinal absorption of aluminium was shown to increase in various pathological conditions, such as AD (Moore et al. 2000). As an example, a low pH will enhance the solubility of aluminium species then increasing aluminium absorption. Small organic acids also present in the diet of man, including citrate, lactate, and ascorbic, gluconic, malic, oxalic, and tartaric acids, are able to prevent its precipitation during transit as they complex with the metal, increasing its absorption from the gastrointestinal tract (Deng et al. 2000, Venturini-Soriano and Berthon 2001, Whitehead et al. 1997), and to aument tissue retention of aluminium in rats orally dosed with aluminium (Domingo et al. 1991, 1994). On the other hand phosphorus, silicone and other dietary factors such as phytate and polyphenols seem to decrease absorption (Yokel and O‟Callaghan 1998, Powell and Thompson 1993, Powell
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INTRODUCTION
et al. 1993), probably through formation of insoluble complexes with aluminium ion in the gut (Schaefer et al. 1988). Three mechanisms, reviewed by Greger and Sutherland (1997), were proposed to explain the increase in aluminium absorption provoked by citrate: enhanced aluminium solubility in the gastrointestinal tract, transport of aluminium citrate into mucosal cells, and opening of epithelial tight junctions that are present between mucosal cells (Taylor et al. 1998). Aluminium absorption does not seem to happen in the stomach where most aluminium is converted to soluble monomolecular species at low pH (Froment et al. 1989). At near-neutral pH aluminium precipitation occurs in the intestine. Consequently, the small portion of aluminium accessible for transport is the part that has been complexed with organic molecules in the stomach, allowing it to remain soluble at higher pH of the small intestine (Reiber et al. 1995). The primary site of aluminium absorption is the proximal intestine (Greger and Sutherland 1997). The precise mechanism of gastrointestinal absorption is not yet fully known. It has been suggested that intestinal absorption of aluminium occurs paracellularly along enterocytes and through tight junctions by passives processes (Exley et al. 1996) and transcellularly through enterocytes involving passive facilitated and active transport processes, such as calcium uptake and sodium transport processes, and a role for transferrin (Greger 1993, Greger and Sutherland 1997). Interestingly, it was suggested that each aluminium species likely has its own absorption mechanism (Van der Voet 1992).
Intranasal absorption Inhalation
exposure
to
aluminium
occurs
from
cosmetic
(aerosols),
environmental and occupational sources (fumes, dusts, flakes). Inhaled aluminium was suggested to accumulate in the brain through absorption via the olfactory system (Roberts 1986, Exley et al. 1996) or through systemic absorption via the lung epithelia (Gitelman et al. 1995) and through the gastrointestinal tract as particulates are swallowed (Rollin et al. 1993). Pulmonary absorption seems to be more efficient than gastrointestinal absorption. Actually, Jones and Benett (1986) estimated that 58
INTRODUCTION
approximately 3% of aluminium is absorbed into the blood from the lung. Although there is still controversy regarding the ability of aluminium to enter the brain from nasal cavity, it has been suggested that aluminium may be able of directly entering the brain from the nose through olfactory neurons. These latter, which are the only part of the CNS with direct contact to external milieu, are located in the roof of the nasal cavity and project to the olfactory bulb. These neurons synapse with complex pathways in the olfactory bulb which subsequently project to other cerebral areas, such as the olfactory cortex, cortex, and hippocampus. A few studies tried to demonstrate that aluminium distribution in the brain occurs through olfactory nerve uptake, axonal and transsynaptic transport. Absorption of aluminium from the olfactory pathway has been studied in rabbits exposed to aluminium lactate application in the upper nasal cavity for one month. This resulted in aluminium accumulation in the olfactory bulb, pyriform cortex, hippocampus and cerebral cortex (Perl and Good 1987) although this prolonged exposure may probably have led to mechanical disruption of the olfactory epithelia (Lewis et al. 1994). Rats exposed to aluminium acetylacetonate had aluminium deposits in the olfactory bulb, ponsmedulla and hippocampus (Zatta et al. 1993). One nose-only exposure study showed that aluminium was also distributed to the brain stem of rats using aluminium chlorohydrate (Divine et al. 1999).
Dermal absorption Aluminium chloride was shown to be absorbed through the skin when applied to the skin of mice, and to accumulate in both serum and brain, especially in the hippocampus (Anane et al. 1995). Nevertheless, systemic absorption of the metal may have been enhanced by mice shaving prior to its application. As aluminium chlorhydrate is the active ingredient extensivey used in antiperspirants, the skin was predicted to be another route of aluminium entry into the systemic circulation (Exley 2004b). Aluminium chlorhydrate is thought to precipitate inside the eccrine sweat glands and to form insoluble aluminium hydroxyde, which then physically blocks the sweat duct (Quartrale 1988, Teagraden et al. 1982) but its efficacy in reducing perspiration may also be due to chemical inhibition of the sweat gland (Strassburger and
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INTRODUCTION
Coble 1987). Transdermal absorption of only 0.012% has been reported after a one-time underarm application of
26
Al chlorhydrate (Flarend et al. 2001) while a case report
showed that transdermal uptake of aluminium may also be important (Guillard et al. 2004).
Distribution of aluminium in the body Once absorbed into the bloodstream, aluminium circulates bound to various plasma proteins: 93% is bound to transferrin, 6% to citrate and the remaining to hydroxide and phosphate (Harris et al. 2003). The metal is distributed unequally to all tissues within the body throughout normal and aluminium-intoxicated individuals (Alfrey et al. 1980, Di Paolo et al. 1997), and aluminium-treated experimental animals (Greger and Sutherland 1997). The highest levels of aluminium in mammalian tissues are found in the skeleton and lungs, approximately 50% and 25% of the 30 to 50 mg aluminium body burden in the healthy human subject (Alfrey 1984, Ganrot 1986, ATSDR 1999). Aluminium also accumulates in human brain, skin, lower gastrointestinal tract, lymph nodes, adrenals, and parathyroid glands (Tipton and Cook 1963, Hamilton et al. 1973, Cann et al. 1979, Alfrey 1980). Aluminium accumulation in different target organs varies with the aluminium salt administered, species studied and route used, dose and duration of exposure (Ding and Zhu 1997, Yokel and McNamara 1988), but also with age, kidney function, disease status, and dietary compounds (Greger 1993). The human brain contains lower levels of aluminium when compared to other organs (Walker et al. 1994, Andrási et al. 2005, Yokel and McNamara 2001). In the case of dialysis encephalopathy, this concentration may aument drastically (Alfrey et al. 1976).
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INTRODUCTION
Excretion As insoluble aluminium hydroxyl coumpounds are formed at neutral pH most of the dietary aluminium is excreted in the faeces without ever being absorbed. If renal functions are not compromised approximately 95% of the absorbed aluminium is quickly excreted in the urine by kidneys, presumably as aluminium citrate. Biliary system accounts for less than 2% of total aluminium elimination (Kovalchik et al. 1978, Priest et al. 1995, Yokel et al. 1996). Decreased renal functionality increases the risk of aluminium accumulation and toxicity (Greger and Sutherland 2007). Indeed, dialysis encephalopathy syndrome (DES) was developed by renal-impaired people who received aluminium in dialysis fluids or parenterally (Alfrey et al. 1976).
Elimination rate Aluminium accumulation is not only due to impaired renal functions or exposure to high quantities of aluminium but also occurs physiologically with aging (McDermott et al. 1979). Aluminium contents of brain, serum, lungs, blood, liver, kidneys, and bone have been demonstrated to increase with age (Markesbery et al. 1984, Zapatero et al. 1995, Greger and Sutherland 1997, Shimizu et al. 1994, U. S. Public Health Service 1992, Stitch 1957, Tipton and Shafer 1964, Roider and Drasch 1999, Markesbery et al. 1981) and younger individuals absorbe less aluminium than older people. Actually, it has been estimated that aluminium deposits in the brain at a rate of 6 μg per year of life (Edwardson 1991). This increasing body burden with age in the brain may be produced by a slow, or no, elimination of aluminium coupled to a continued exposure to the metal and a decreased ability to remove the metal from the brain with age. Different aluminium half-lives (t½) have been reported suggesting that there is more than one compartment of aluminium storage from which the metal is slowly eliminated (Wilhelm et al. 1990, Ljunggren et al. 1991, Priest et al. 1995). The t½ of aluminium elimination positively correlates with the duration of the exposure as longer t½ were observed when the duration of sampling after exposure was increased. Bone stores about 58% of the human aluminium body burden and its aluminium clearance is more rapid than from brain, which is logical regarding to bone turnover and lack of neuron turnover.
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INTRODUCTION
Aluminium influx and efflux into the brain The brain has lower aluminium concentrations (about 1%) than many other tissues (Yokel and McNamara 2001), but it is an important target organ for aluminiumtoxicity. Even as the BBB is highly selective to a great variety of substances, including metals, aluminium is able to cross it and enter the brain from blood (Yokel 2002b) and to accumulate in nerve and glial cells. Although the mechanism(s) responsible for aluminium transport at the BBB has not been clarified yet, it has been reported that aluminium can penetrate into the brain as a complex with transferrin by a receptormediated endocytosis (Roskams and Connor 1990) and also bound to citrate via a specific transporter, being the system Xc (L-glutamate/L-CySH exchanger) the most recently accepted candidate (Nagasawa et al. 2005). There is also evidence for transporter-mediated efflux from the brain, the organic anion transporting polypeptide (oatp) family was suggested to be a candidate (Yokel 2006). The existence of a long apparent half-life of aluminium in brain tissue has been used to explain its easy accumulation into the brain following aluminium administration (Yokel et al. 2001b, Baydar et al. 2003, Sánchez-Iglesias et al. 2007b). The elimination half-life of aluminium from human brain is calculated to be seven years (Yokel and McNamara 2001). This assumption and the long life of neurons could be involved in the elevated levels of aluminium found in the brain of some patients suffering PD (Hirsh et al. 1991, Good et al. 1992, Yasui et al. 1992) and AD (Crapper et al. 1973, Perl and Brody 1980), a statement that, on the other hand, will not be understoo as the principal cause of those disorders. Since aluminium and its compounds are widely distributed in the environment (food, drinking water, airborne contaminants) and extensively used in a variety of products and processes (antiperspirants, antacids, intravenous solutions), it has aroused considerable health concern, due to both its common exposure and its particularly reported ability to cause neurodegeneration (Exley 1999, Yokel 2000, Zatta et al. 2003, Kawahara 2005). As we have previously seen, the daily reported mean dietary intake of
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INTRODUCTION
3.5 mg may be increased by the frequent use of aluminium-containing antiperspirants and non-prescription drugs (Weburg and Berstad 1986, Flarend et al. 2001), as well as by occupational exposure to this metal (Meyer-Baron et al. 2007).
Putative mechanisms of aluminium neurotoxicity No biological function has yet been attributed to aluminium, for which reason it is considered a nonessential metal (Yokel 2002a). However, aluminium neurotoxicity was first outlined by Dölken in 1897. Since then, aluminium accumulation in the brain has been repetitively linked to various neurodegenerative diseases (Yokel 2000, Zatta et al. 2003, Kawahara 2005). As a matter of fact, this non-redox active metal has been demonstrated to be a toxicant that is implicated in dialysis encephalopathy (Alfrey et al. 1976), osteomalacia (Parkinson et al. 1979), non-iron responsible anemia (Elliot et al. 1978), and also linked to many other diseases including AD (Exley 1999, Flaten 2001, Gupta et al. 2005), amyotrophic lateral sclerosis (Kurland 1988), and PD (Dexter et al. 1989, Yasui et al. 1992, Good et al. 1992). Aluminium was shown to be overaccumulated in the brain of post-mortem patients compared to healthy individuals (Perl et al. 1982, Yasui et al. 1992, Ward and Mason 1987) Many reviews have been published on the toxic effects of aluminium. Nevertheless, and despite all hitherto reported data concerning aluminium neurotoxicity, no single unifying mechanism responsible for its neurotoxicity has been identified. Therefore, several interlinked hypotheses have been proposed, highlighting distinct events as a basis for the beginning of aluminium toxic brain damage.
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INTRODUCTION
Aluminium and oxidative stress The model involving aggravation of oxidative stress is among the most recognized hypothesis of aluminium neurotoxicity but the precise molecular mechanism by which it causes oxidative damage into the brain remains uncertain. Actually, a large number of studies confirmed the existence of a state of oxidative stress in most of the neurodegenerative disorders in which aluminium is present in relative high quantities. Numerous publications have detailed an increase in the formation of ROS after aluminium exposure both in vivo and in vitro (Katyal et al. 1997, Flora et al. 2003, Ogasawara et al. 2003, Nehru and Anand 2005). However, the reported results as a whole appear controversial, to such an extent that both pro-oxidant (Zatta et al. 2002, Exley 2004a) and antioxidant (Oteiza et al. 1993a, Abukadar et al. 2004a) properties have been attributed to this metal.
The brain: a target for aluminium The brain is a main target for aluminium neurotoxicity as it is highly susceptible to oxidative insult for several reasons: (a) a high oxygen turnover as the brain consumes a proportionally larger amount of oxygen than other organs, around 20% of the body‟s oxygen (Halliwell 1992), (b) a low mitotic rate, (c) low concentrations/activities of brain antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), (d) (Halliwell and Gutteridge 1985) a large amount of highly oxidizable polyunsaturated fatty acids in neuronal cell membranes (Table 5), and (e) a high brain content of iron (Youdim 1988). Several hypotheses have been given to explain the possible link between aluminium and the promotion of oxidative stress (Exley 2004a). Actually, even though aluminium is not a transition metal, and consequently does not undergo redox reactions, it can cause oxidative stress both in vivo and in vitro through multiple mechanisms. As examples, it has been shown to stimulate in vitro iron-induced and non-iron-induced lipid peroxidation (Gutteridge et al. 1985, Verstraeten and Oteiza 2000, Meglio and
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INTRODUCTION
Oteiza 1999), non-iron-mediated oxidation of NADH (Meglio and Oteiza 1999, Kong et al. 1992), and non-iron-mediated formation of the OH (Méndez-Álvarez et al. 2002).
Table 5:
Lipid composition of normal adult human brain (dry weight) (Zatta et al. 2002)
Gray matter (%)
White matter (%)
22
27.5
Total phospholipids
69.5
45.9
Phosphatidylserine
8.7
7.9
Galactocerebroside
5.4
19.8
Galactocerebroside sulphate
1.7
5.4
Cholesterol
Aluminium catalyses iron-driven biological oxidations Aluminium was also shown to potentiate the capacity of pro-oxidants transition metals, such as iron and copper which are present in most cell compartments, to produce oxidative stress (Bondy and Kirstein 1996, Bondy et al. 1998). It was hypothesized that colloidal aluminium may complex these pro-oxidant metals and permit them to participate in Fenton reaction for an extended time (Yang et al. 1999, Campbell et al. 2001).
Aluminium stimulates superoxide-/non-iron-driven biological oxidations We have seen that O2●─ is the ROS with the lowest oxidant capacity but it can undergo a one-electron transfer to generate H2O2 which can in turn through the Fenton reaction and in the presence of reduced metal ions, be converted to ●OH, increasing its redox potential. Various studies proposed that aluminium could enhance the O2●─mediated oxidation in different systems that generate this ROS: the photochemical decomposition of rose Bengal (Kong et al. 1992, Meglio and Oteiza 1999), the autoxidation of 6-OHDA (Méndez-Álvarez et al. 2002), the vanadium-mediated oxidation of NADH (Adler et al. 1995), and the xanthine/xanthine oxidase system
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INTRODUCTION
(Kong et al. 2002). In the same way, trivalent cations chemically and physically related to aluminium (lanthanum, gallium and scandium) were shown to increase O2●─ oxidative capacity (Meglio and Oteiza 1999).
Aluminium-superoxide complex theory It was hypothesized that the formation of a complex between Al3+ and O2●─ may explain the pro-oxidant activity of aluminium and also the catalytic activity connecting both superoxide-driven and iron-driven biological oxidations. Aluminium is a strong Lewis acid which may react with the superoxide anion and form an aluminium superoxide anion, which is a more potent oxidant than the superoxide anion on its own (Kong et al. 1992, Exley 2004a). Al3+ + O2●─ ↔ AlO2●2+ As an example, the iron-supported oxidation of DA to melanin was shown to be facilitated by aluminium (Di and Bi 2003). The subsequent binding of melanin with aluminium leads to an increased melanin-induced lipid oxidation in a process mediated by an Al–O2●─ complex (Meglio and Oteiza 1999, Verstraeten et al. 2008). Aluminium inhibits the antioxidant enzymes and others Additionally, aluminium also appears to affect the activities of several antioxidant enzymes in different parts of the brain and cause oxidative damage (Nehru and Anand 2005, Julka and Gill 1996a, Atienzar et al. 1998, Moumen et al. 2001, Gómez et al. 2005, Sánchez-Iglesias et al. 2009). The decrease of the activity of antioxidative enzymes may facilitate the propagation of lipid peroxidation. In addition, the ability of aluminium to affect the functionality of mitochondria has also been documented (Niu et al. 2005).
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INTRODUCTION
Aluminium as a cell membrane menace Numerous studies performed both in vitro and in vivo considered that the principal consequences of aluminium on the cerebral functions are mediated through damage to cell membranes. Metals without redox capacity as aluminium were suggested to make fatty acids more available to the action of free radicals and therefore ease the spread of lipid peroxidation (Oteiza et al. 1993a, Ohyashiki et al. 1998). Actually, aluminium binds to membrane components and modifies both membrane biophysical properties and dynamics. Binding of aluminium is enhanced by the presence of polar head groups with negative charge and happens via formation of both cis and trans complexes (Oteiza 1994, Verstraeten 2000). This metal was shown to bind through electrostatic interactions preferentially to the phosphatidylserine, phosphatidic acid, and poliphosphoinositides found in biological membranes because of their overall negative charge due to their carboxylate or phosphate moieties. Transinteractions or intervesicle interactions are not specifically implicated in lipid oxidation as they result in membrane aggregation and fusion (Verstaeten and Oteiza 1995). Actually, superficial charges are neutralized by aluminium which causes the intercrossing and dehydration of neighboring phosphatidylserine molecules. On the other hand, cis-interactions within the same vesicle lead to the lateral reorganization of these phospholipids (lipid clustering) and formation of distinct microdomains enriched in acidic phospholipids with lower membrane fluidity (Verstraeten and Oteiza 1995, Verstraeten et al. 1997a, 1998). The local accumulation of poly-unsaturated fatty acids caused by aluminium makes the phospholipids higly susceptible to ROS, leading to the propagation of lipid peroxidation. Aluminium was also shown to modify the biophysical properties of membranes containing galactocerebrosides or polyphosphoinositides (Verstraeten et al. 1998, 2003, Verstraeten and Oteiza 2002), myelin and synaptosomal membranes, which may result in injurious effects for neurotransmission (Ohba et al. 1994, Julka and Gill 1996b, Verstraeten et al. 1997b, Silva et al. 2002, Pandya et al. 2004).
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INTRODUCTION
As mentioned before, aluminium is able to stimulate iron-induced oxidations. In the peroxidation process both metals are thought to act synergistically: while the aluminium binding to neuronal membranes is attended to facilitate its attack by ironmediated oxidative damage, the subsequent oxidation of the membrane will consecutively increase its binding to aluminium, hence exacerbating peroxidation (Figure 22). Figure 22: Effects of aluminium and iron on the membrane peroxidation (Zatta et al. 2002, Oteiza et al. 2004)
Lipid peroxidation is particularly active in the brain where it induces: a) changes in the structure of biological membranes resulting in the loss of membrane fluidity, b) changes of the structural order of membrane lipids (Palmeira and Oliveira 1992), c) variations in membrane potential, d) an increase in membrane permeability to ions (Marshansky et al. 1983), e) modifications in the activity of membrane-bound enzymes (Pereira et al. 1996), and f) alterations in receptor functions.
Aluminium affects cell signaling Another mechanism that has been suggested to be involved in aluminium toxicity is the alteration of specific cell signaling cascades. Aluminium interferes with phosphoinositide signal transduction pathway (Nostrandt et al. 1996, Quintal-Tun et al. 2007). This metabolic pathway mediated by the enzyme phosphatidylinositol-specific phospholipase C (PI-PLC) renders inositol triphosphate (IP3) and diacylglycerol, two important intracellular second messengers. IP3 is in charge of the intracellular
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INTRODUCTION
mobilization of Ca2+ with the consequent activation of multiple signals, whereas diacylglycerol activates enzymes such as protein kinase C (PKC). Aluminium leads to a decrease in the hydrolysis of phosphatidylinositol biphosphate (PIP2) both in vivo and in vitro (McDonald and Mamrack 1988, Shafer et al. 1993, McDonald and Mamrack 1995, Shafer and Mundy 1995, Nostrandt et al. 1996). As we have seen before, aluminium preferential binding to negative charges of polyphosphoinositides causes partial neutralization of negative charge, clustering, and increased local concentration of these lipids. All these together result in a limited accessibility of PI-PLC to its substrates and the subsequent decreased in the enzyme activity (Figure 23) (Verstraeten and Oteiza 2002, Verstraeten et al. 2003). Signaling cascades involving either binding of regulatory proteins to polyphosphoinositides in the membranes or involving phosphatidylinositol (PI)-derived second messengers may be negatively altered by aluminium. Figure 23: PIP2 hydrolysis altered by aluminium (Oteiza et al. 2004)
Inflammation generally accompanies neurodegenerative diseases. One of the initial events in the cascade leading to inflammatory responses is the activation of transcription factors. The cytokine TNF-α activates transcription factor NF-κB which consecutively accelerates the transcription of specific genes involved in inflammation, such as other cytokines, iNOS, and complement factors by translocating to the nucleus and binding to their promoter regions. Aluminium was reported to cause an inflammatory response in the brain both in vivo and in vitro (Yokel and O‟Callaghan 1998, Ghribi et al. 2001a, Platt et al. 2001, Campbell et al. 2002, Becaria et al. 2003, Johnson and Sharma 2003). The metal activates NF-κB and TNF-α expression leading to cell death and proliferation of reactive glial cells rising tissue damage (Campbell et al. 2002, 2004). 69
INTRODUCTION
The signal transduction pathway of mitogen-activated protein kinase (MAPK) plays also an important role in the apoptosis in neurons or astrocytes. Aluminium was demonstrated to activate in cultured cortical neurons one of the important members in MAPK family, the stress-activated protein kinase c-jun N-terminal kinase (SAPK/JNK) (Fu et al. 2003), whose phosphorylation and dephosphorylation are considered as the molecular key in stress signal transduction. SAPK/KNK activates its downstream transcription factor c-jun, which is the important component of AP-1. This latter modulates the expression of target genes and participates in the regulation of cell differentiation and apoptosis. Neuronal accumulation of aluminium affects mitochondria integrity and functionality (reviewed by Kumar and Gill 2009). The metal enters into the neuron upon cell depolarization and inhibits Na+/Ca2+ exchange thus inducing an extreme accumulation of mitochondrial Ca2+. This triggers the opening of the mitochondrial transition pore (MTP) and the consequent release of cytochrome c leading finally to activation of the caspase family proteases. Studies that used intracisternal injection of the aluminium-maltolate complex have shown that aluminium targets mitochondria. Aluminium-maltolate is a lipophilic complex stable at physiological pH and proposed to be formed in the gastrointestinal tract. This neurotoxic complex produces cytoskeletal alterations (Klatzo et al. 1965, Savory et al. 1996, 1998) leading to tangle formation and cell apoptosis (Johnson et al. 2005). Aluminium-maltolate induces cytochrome c translocation, increased expression of the proapoptotic protein Bax, and decreased expression of the antiapoptotic protein Bcl-2, finally leading to cell apoptosis (Ghribi et al. 2001a, 2002). In addition, aluminium also affects the endoplasmic reticulum (ER), the major storage location for calcium, which also contains members of the Bcl-2 family, such as Bcl-2 and Bcl-XL. The stress induced by aluminium-maltolate activates caspase 12 leading to a specific type of ER-mediated cell death by apoptosis (Ghribi et al. 2001b, 2001c, 2002).
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INTRODUCTION
Aluminium impairs neurotransmission Aluminium has a negative impact on the main steps of the neurotransmission event which takes place at the synapse, such as synthesis and storage of neurotransmitters, triggered release from the presynaptic terminal, interaction with receptors on the postsynaptic cell, and inactivation of neurotransmitters (Gonçalves and Silva 2007). The metal may alter the physical properties of synaptic membranes which could influence the release and/or uptake of neurotransmitters, or directly inhibit the enzymes in charge of the synthesis, utilization and degradation of these molecules. There are evidences demonstrating that this metal disturbs some crucial events of DA neurotransmission. The DA metabolism appears to be altered in animal models of aluminium: DA levels are reduced by 40% in the striatum (Ravi et al. 2000) and the concentration of DA metabolites such as dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) are lower in the hypothalamus of treated animals (Tsunoda and Sharma 1999). Besides, the ability of aluminium to affect the expression of DA receptors D1 and D2 (Kim et al. 2007) and to inhibit DA-β-hydroxylase, the enzyme in charge of converting DA into noradrenaline (Milanese et al. 2001), has also been documented. Aluminium interferes also with glutamatergic, cholinergic, and GABAergic metabolisms. Actually, aluminium exposure in rats leads to decreased acetylcholine synthesis and degradation, reduction of muscarinic acetylcholine receptors (Julka et al. 1995), increased contents of glutamine and glutamate, and decreased GABA level (El-Rahman 2003, Nayak and Chatterjee 2003). Alterations of calcium metabolism may also be of importance for aluminium neurotoxicity as calcium has a crucial role in neurotransmitter release. As an example, aluminium inhibits GABA synaptosomal release and uptake as a consequence of the inhibition of Ca2+/CaMdependent calcineurin activity (Cordeiro et al. 2003).
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AIMS
AIMS
AIMS OF THE PRESENT THESIS The main objectives of this thesis were distributed in three chapters as follows:
Chapter 1 The first principal aim is to determine the kinetics of the oxidative damage induced in a 6-OHDA model of PD and quantify the resulting oxidative effects in order to set up the accurate post-injection time when studying the oxidative effects of aluminium. To achieve this aim we have stablished the following specific objectives: 1) To analyse the time-course of the oxidative damage caused by unilateral and intrastriatal administration of 6-OHDA (6 μg in 5 μl of sterile saline containing 0.2% ascorbic acid) in both the ipsilateral and contralateral sides of both striatum and ventral midbrain of the rat. 2) To quantify the changes observed in the indices of lipid peroxidation (TBARS) and oxidative status of proteins (PCC and PTC) in the time-course of brain oxidative damage induced by 6-OHDA injection in the experimental model of PD mentioned above.
Chapter 2 The second main objective is to elaborate a dosage procedure that ensures a significant accumulation of aluminium into the brain and to establish its exact distribution in different areas of the rat brain. In this case, the specific objective is: 3) To evaluate the precise regional accumulation of the absorbed aluminium in cerebellum, ventral midbrain, cortex, hippocampus and striatum of rats following the use of two different administration routes, oral and intraperitoneal.
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AIMS
Chapter 3 The third major aim of this thesis is to clarify the capacity of aluminium to modify the oxidant level of certain brain regions and to augment the striatal DAergic neurodegeneration in a 6-OHDA model of PD. The specific objectives to reach this aim are: 4) To investigate the in vivo effects induced by aluminium on indices of oxidative stress by quantification of lipid peroxidation (TBARS) and the oxidant status of proteins (PCC, PTC), in the cerebellum, ventral midbrain, cortex, hippocampus, and striatum of rats. 5) To assess the in vivo effects of aluminium on the activity of certain antioxidant enzymes, such as SOD, GPx and CAT, in the cerebellum, ventral midbrain, cortex, hippocampus, and striatum of rats. 6) To measure the in vitro effects of aluminium on the activity of some antioxidant enzymes (SOD, GPx, CAT) and the monoamine oxidase activity (MAO-A and MAO-B). 7) To study the ability of aluminium to potentiate the capacity of 6-OHDA administered in the third ventricle in an experimental model of PD to cause oxidative stress (lipid peroxidation and protein oxidation) in ventral midbrain and striatum and to induce neurodegeneration in striatal DAergic terminals.
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OBJETIVOS
OBJETIVOS
OBJETIVOS DE LA PRESENTE TESIS Los objetivos principales de esta tesis fueron distribuidos en tres capítulos de la siguiente manera:
Capítulo 1 El primer objetivo principal es determinar la cinética de las lesiones oxidativas producidas en un modelo experimental de Parkinson con 6-OHDA y cuantificar los efectos oxidativos resultantes. Este estudio nos permitirá establecer el tiempo exacto después de la inyección con 6-OHDA en el que estudiar los efectos oxidativos del aluminio. Los objetivos concretos son: 1) Analizar el curso temporal del daño oxidativo causado por la administración unilateral e intrastriatal de 6-OHDA (6 µg en 5 µl de salino estéril con 0.2% ácido ascórbico) en los lados ipsilaterales y contralaterales del estriado y mesencéfalo ventral de la rata. 2) Cuantificar los cambios observados en los níveles de peroxidación lipídica (TBARS) y del estado oxidativo de las proteínas (contenidos de grupos carbonilo y tiol en proteínas) durante el curso temporal del daño oxidativo cerebral inducido por la inyección de 6-OHDA en el modelo experimental de la enfermedad de Parkinson mencionado anteriormente. Capítulo 2 El segundo objetivo principal consiste en elaborar un régimen de dosis en el que se garantice una acumulación significativa de aluminio en el cerebro y establecer la distribución exacta del metal en las regiones cerebrales de las ratas. En este caso, el objetivo concreto es:
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OBJETIVOS
3) Evaluar de forma precisa la acumulación regional del aluminio absorbido en el cerebelo, mesencéfalo ventral, corteza, hipocampo y estriado de las ratas después de la utilización de dos vías distintas de administración, oral e intraperitoneal. Capítulo 3 El tercer objetivo principal de esta tesis consiste en esclarecer la capacidad del aluminio para alterar el estado oxidativo de ciertas regions cerebrales y para aumentar la neurodegeneración dopaminérgica estriatal en un modelo experimental de Parkinson con 6-OHDA, siendo los objetivos concretos: 4) Investigar los efectos in vivo inducidos por el aluminio en los índices de estrés oxidativo, mediante la cuantificación de la peroxidación lipídica (TBARS) y el estado oxidativo de las proteínas (contenidos en grupos carbonilo y tiol en proteínas), en cerebelo, mesencéfalo ventral, corteza, hipocampo y estriado de rata. 5) Evaluar los efectos in vivo del aluminio sobre la actividad de determinados enzimas antioxidantes, tales como la superóxido dismutasa, la glutatión peroxidasa y la catalasa, en cerebelo, mesencéfalo ventral, corteza, hipocampo y estriado de rata. 6) Cuantificar los posibles efectos in vitro del aluminio sobre la actividad de los enzimas antioxidantes estudiados (superóxido dismutasa, glutatión peroxidasa y catalasa) y sobre la actividad de las monoamino oxidasas A y B. 7) Estudiar la capacidad del aluminio para aumentar la capacidad de la 6-OHDA administrada en el tercer ventrículo en un modelo experimental de la enfermedad de Parkinson para causar estrés oxidativo (peroxidación lipídica y oxidación protéica) en el mesencéfalo ventral y estriado y para inducir neurodegeneración en las terminales dopaminérgicas estriatales.
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CHAPTER 1
CHAPTER 1
Time-course of brain oxidative damage caused by intrastriatal administration of 6-hydroxydopamine in a rat model of Parkinson’s disease Sofía Sánchez-Iglesias,* Pablo Rey,† Estefanía Méndez-Álvarez,* José Luis Labandeira-García† and Ramón Soto-Otero* *Laboratory of Neurochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain †Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
Neurochem. Res. (2007) 32, 99–105.
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ABSTRACT The unilateral and intrastriatal injection of 6-OHDA is commonly used to provide a partial lesion model of PD in the investigation of the molecular mechanisms involved in its pathogenesis and to assess new neuroprotective treatments. Its capacity to induce neurodegeneration has been related to its ability to undergo autoxidation in the presence of oxygen and consequently to generate oxidative stress. The aim of the present study was to investigate the time course of brain oxidative damage induced by 6-OHDA (6 μg in 5 μl of sterile saline containing 0.2% ascorbic acid) injection in the right striatum of male Sprague-Dawley rat. The results of this study show that the indices of both lipid peroxidation (TBARS) and protein oxidation (PCC and PTC) increase simultaneously in the ipsilateral striatum and ventral midbrain, reaching a peak value at 48-h post-injection for both TBARS and PCC, and at 24 h for PTC. A lower but significant increase was also observed in the contralateral side (striatum and ventral midbrain). The indices of oxidative stress returned to values close to those found in controls at 7-day postinjection. These data show that the oxidative stress is a possible triggering
factor
for
the
neurodegenerative
process
and
the
retrograde
neurodegeneration observed after the first week post-injection seems to be a consequence of the cell damage caused during the first days post-injection. Finally, the optimal time to assess brain indices of oxidative stress (TBARS, PCC and PTC) in this model is 48-h post-injection.
Keywords: Parkinson‟s disease, 6-hydroxydopamine, oxidative damage, lipid peroxidation, protein oxidation.
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INTRODUCTION 6-OHDA
(2,4,5-trihydroxyphenylethylamine;
6-OHDA)
is
a
selective
catecholaminergic neurotoxin widely used to produce DAergic lesions in the nigrostriatal system (Dauer and Przedborski 2003). The main use of these lesions is to create experimental models of PD that provide insight into the molecular mechanisms involved in the development of PD in order to test new strategies for DAergic neuroprotection, and to experiment with transplantation approaches (Aebischer et al. 1991, He et al. 2001, Soto-Otero et al. 2002, Muñoz et al. 2004, López-Real et al. 2005). The structural similarity of 6-OHDA with both DA and noradrenaline makes it an appropriate ligand for the plasma membrane transporter systems of DA (DAT) and noradrenaline (Luthman et al. 1989). This feature, together with the inability shown by 6-OHDA to cross the BBB (Garver et al. 1975), makes the protocol chosen for a specific DAergic lesion in the nigrostriatal system extremely important. The main protocol used consists of the stereotaxic intracerebral injection of the toxin into a specific area of the nigrostriatal systems, which includes the stria tum, the medial forebrain bundle or the SN (Javoy et al. 1976). The intrastriatal injection of 6-OHDA is generally performed unilaterally, using the contralateral side as a control (Ungerstedt 1971). It has been shown that the intrastriatal administration of 6-OHDA causes a rapid degeneration of nigrostriatal terminals as early as 24 h, and the loss of tyrosine hydroxylase immunoreactivity (TH-ir) increases for up to 5 days following the lesion (Ichitani et al. 1991). Presumably, the neurotoxicity of 6-OHDA is attributed to its ability to generate ROS, and it is a well-known fact that under physiologyical conditions this compound is rapidly oxidized by molecular oxygen to give H2O2, OH and the corresponding pquinone. Although, the Fenton reaction could be involved in the formation of the hazardous OH during the autoxidation of 6-OHDA, this is done without the involvement of the ferrous ion or any other transitionmetal ion (Marti et al. 1997). At this point, it seems interesting to highlight the reported ability of ascorbate to enhance the production of ROS by 6-OHDA (Soto-Otero et al. 2000, Méndez-Álvarez et al.
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2001), particularly due to the fact that 6-OHDA is always administered in a saline solution containing about 2% of ascorbate. In these cases, the presence of ascorbate sets a redox-cycling, which regenerates 6-OHDA from its p-quinone leading to a continuous production of ROS. Moreover, the presence of the enzyme dehydroascorbate reductase in the brain may contribute to sustaining this redox-cycling. Although, this is the molecular mechanism generally accepted to explain the ability of 6-OHDA to produce oxidative stress and consequently responsible for its neurotoxicity, it has been also reported that 6-OHDA can act directly by inhibiting the mitochondrial respiratory chain at the level of complex I (Glinka and Youdim 1995, Glinka et al. 1996, Glinka et al. 1998). Assuming the reported capacity of complex I inhibitors to increase the leakage of superoxide anions from the electron transport chain (Brand et al. 2004), this latter mechanism could also contribute to increase the ability of 6-OHDA to produce ROS and consequently to generate oxidative stress. Recent reports refer to the potential contribution of ER stress to the cell death induced by 6-OHDA (Yamamuro et al. 2006). Despite the widespread use of the intrastriatal injection of 6-OHDA to obtain an experimental model of parkinsonism and an awareness of the morphological changes following its administration (Jonsson 1983, Jeon et al. 1995), no data has been reported on the kinetics of the oxidative damage it induces in the nigrostriatal system. However, this information is crucial when this model is exploited to assess the anti-parkinsoniam properties of new drugs (Jiang et al. 1993) or the benefit of transplantation or gene therapy to repair the damaged pathways (He et al. 2001, Björklund et al. 2002). In the light of this, the aim of the present study was to investigate the time-course of the oxidative damage caused by unilateral and intrastriatal administration of 6-OHDA in the ipsilateral and contralateral side of both striatum and ventral midbrain, and also includes a quantification of the changes observed in the indices of lipid peroxidation (TBARS) and oxidative status of proteins (PCC and PTC).
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MATERIALS AND METHODS Chemicals 6-OHDA hydrochloride, ascorbic acid, thiobarbituric acid (TBA), butylated hydroxytoluene
crystalline
(BHT),
2,4-dinitrophenylhydrazine
desferrioxamine,
1,1,3,3-tetramethoypropane,
hydrochloride,
5,5‟-dithiobis-(2-nitrobenzoic
acid),
sodium dodecylsulfate, EDTA, and bovine serum albumin (BSA) were purchased from Sigma Chemical Co. (St. Louis, MO, USA). Guanidine hydrochloride was from Aldrich Chemical Co. (Milwaukee, WI, USA). The water used for the preparations of solutions was of 18.2 MΩ (Milli-RiOs/Q-A10 grade, Millipore Corp., Bedford, MA, USA). All remaining chemicals used were of analytical grade and were purchased from Fluka Chemie AG (Buchs, Switzerland).
Animal treatment A total of 32 male Sprague-Dawley rats, each weighing about 200 g, were used. All the experiments were carried out in accordance with the „„Principles of laboratory animal care‟‟ (NIH publication No. 86–23, revised 1985) and approved by the corresponding committee at the University of Santiago de Compostela. Rats were stereotaxically injected in the right striatum with 6 μg of 6-OHDA in 5 μl of sterile saline containing 0.2% ascorbic acid. Stereotaxic coordinates were 1.0 mm anterior to bregma, 2.7 mm right of midline, 5.5 mm ventral to the dura, and tooth bar at -3.3. The solution was injected with a 5 μl Hamilton syringe couple to a monitorized injector (Stoelting, Wood Dale, IL, USA) and the cannula was left in situ for 5 min after injection. All surgery was performed under equithesin anesthesia (3 ml/kg i.p.). Groups of four rats were decapitated at the following times after injection: 5 min, 1 h, 12 h, 24 h, 48 h, 3 days, and 7 days. A group of four rats (control) was sacrificed immediately after the administration of the saline.
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Brain samples After decapitation, the brain was removed, the striatum and ventral midbrain dissected, and the resulting samples frozen on dry ice. Each sample was immediately sonicated (250 Digital sonifer, Branson Ultrasonic Co., Danbury, CT, USA) with four volumes (w/v) a Na2PO4/KH2PO4 buffer (pH 7.4) isotonized with KCl and containing 200 μM BHT and 200 μM desferrioxamine. These compounds were used to prevent amplification of lipid peroxidation during the progression of the analysis.
Determination of TBARS The TBARS determination was performed spectrophotometrically using a previously published method (Soto-Otero et al. 2002). Briefly, an aliquot of the sample (200 μl) was treated with SDS (8%, w/v) followed by acetic acid (20%) and the mixture vortexed for 1 min. Then, TBA (0.8%) was added and the resulting mixture incubated at 95°C for 60 min. After cooling to room temperature, 3 ml of n-butanol were added and the mixture shaken vigorously. After centrifugation at 4,000 rpm for 5 min, the absorbance of the supernatant (organic layer) was measured at 532 nm using an UVVIS spectrophotometer, model Lambda 35 (Perkin-Elmer Inc., Norwalk, CT, USA). For calibration, a standard curve (5–150 nM) was generated using the malonodialdehyde (MDA) derived by the acid hydrolysis (SO4H2; 1.5%, v/v) of 1,1,3,3-tetraethoxypropane (TEP) and the TBARS results expressed as nmol MDA/mg protein. The protein concentration of the sample was determined according to the method of Markwell et al. (1978), using BSA as the standard.
Determination of protein carbonyl content (PCC) The PCC was assessed spectrophotometrically according to a procedure previously published (Hermida-Ameijeiras et al. 2004). Briefly, an aliquot of the sample was submitted to precipitation of nucleic acids with 1% streptomycin sulfate (1:9, v/v)
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CHAPTER 1
followed by centrifugation at 13,000 rpm. The pellet was then discarded and the supernatant treated with trichloroacetic acid (1 M) followed consecutively by sonication and centrifugation in a microcentrifuge (model E, Beckman Instruments, Palo Alto, CA, USA) at 13,000 rpm for 5 min. The resulting pellet was reconstituted in NaOH (0.5 M) with vigorous vortexing for 3 min. Then, 10 mM 2,4-dinitrophenylhydrazine in 2 M chloric acid was added and the mixture incubated at room temperature for 1 h, in darkness, and with continuous agitation. After the addition of trichloroacetic acid (1 M), the resulting mixture was centrifuged at 13,000 rpm for 5 min. The resulting pellet was washed twice with ethyl acetate : ethanol (1:1, v/v). Then, the washed pellet was reconstituted with 6 M guanidine in a 20 mM KH2PO4 buffer (pH 2.3) and the absorbance of the solution measured at 370 nm. The PCC was calculated from the absorbance data using as absorption coefficient for dinitrophenylhydrazone ε = 22,000 M–1 cm–1 and expressing this parameter as nmol carbonyls/mg protein. Because of the numerous washing steps, protein content in the final pellet was estimated on an HCl blank pellet processed simultaneously using a BSA standard curve in 6 M guanidine, and reading the absorbance at 280 nm.
Determination of protein thiol content (PTC) The PTC of proteins was estimated spectrophotometrically using a modification introduced to a standard assay (Hermida-Ameijeiras et al. 2004). Briefly, an aliquot of the sample (200 μl) was treated with trichloroacetic acid (0.5 M) for protein precipitation. After vortexing and centrifugation at 13,000 rpm for 5 min, the resulting pellet was reconstituted in an 80 mM Na3PO4 and 2 mM EDTA buffer (pH 8.0) containing 70 mM sodium dodecylsulfate. Then, 100 μM 5,5‟-dithiobis-(2-nitrobenzoic acid) in a buffer 100 mM Na3PO4 (pH 8.0) were added and the mixture incubated at room temperature for 20 min with continuous mixing. After centrifugation at 13,000 rpm for 5 min, the absorbance of the resulting solution was measured at 412 nm and the PTC calculated from this data using as absorption coefficient for 2-nitro-5mercaptobenzoic acid ε = 13,600 M–1 cm–1 and expressing the corresponding parameter as nmol thiols/mg protein. 90
CHAPTER 1
Statistical analysis Results were expressed as the mean ± SD from five animals. Statistical differences were tested using one-way ANOVA followed by LSD for multiple comparisons (p < 0.05). All statistical analyses were performed using Sigmastat 3.0 from Jandel Scientific (San Diego, CA, USA).
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CHAPTER 1
RESULTS Effects of 6-OHDA administration on TBARS concentration As shown in Fig. 1, the intrastriatal administration of 6 μg of 6-OHDA in the right striatum caused a significant and progressive increase of TBARS concentration in both right striatum (F(7,24) = 51.73, p < 0.001) and right ventral midbrain (F(7,24) = 72.81, p < 0.001), obtaining a peak-effect 48 h after the injection. Although, the increase in the right striatum was significant at 5 min versus 1 h for ventral midbrain, the augmentation observed after 48 h was higher in the right ventral midbrain (+83%) than in the right striatum (+26%). At 7-day post-injection, the values returned to those of the controls. A significant and progressive increase in the TBARS concentration was also observed in the contralateral side, affecting again to both left striatum (F(7,24) = 10.39, p < 0.001) and left ventral midbrain (F(7,24) = 6.30, p < 0.001). The peak-effect was also observed at 48 h, but the increase was lower (+23% in the left striatum and +26% in the left ventral midbrain). At 7-day post-injection the values returned to the concentrations found in the corresponding controls.
Effects of 6-OHDA administration on PCC The PCC also exhibited a significant and progressive time course increase (Fig. 2), which affected both right striatum (F(7,24) = 57.55, p < 0.001) and right ventral midbrain (F(7,24) = 54.76, p < 0.001). In this case, the increase observed in PCC was not significant till 1-h post-injection. However, the peak-effect was observed once again 48 h after injection, and higher in the right ventral midbrain (+42%) than in the right striatum (+38%). A significant and progressive increase in PCC was also observed in the contralateral side, affecting to both left striatum (F(7,24) = 5.95, p < 0.001) and left ventral midbrain (F(7,24) = 3.48, p < 0.05). However, in this case, although the peakeffect was also observed at 48-h post-injection, the increase found was lower (+12% in
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CHAPTER 1
the left striatum and +11% in the left ventral midbrain). The corresponding concentrations achieved values close to those found in the controls at 7-day postinjection.
Effects of 6-OHDA administration on PTC Figure 3 shows the time-course of the changes observed for PTC in proteins following 6-OHDA administration. As can be seen, a significant and progressive reduction in PTC was found in both right striatum (F(7,24) = 5.06, p < 0.05) and right ventral midbrain (F(7,24) = 25.87, p < 0.001). The maximal decrease for both right striatum (–7%) and right ventral midbrain (–20%) was found at 24 h. Although the peak-effect did not happen at the same time for both TBARS concentration and PCC, the value obtained for PTC at 24 h was not significantly different when compared with that observed 48-h post-injection. The PTC in the contralateral side only exhibited a significant reduction in the left ventral midbrain (F(7,24) = 5.06, p < 0.05), because the changes observed in the left striatum did not reach statistical significance (F(7,24) = 0.87, p > 0.05). Once again, the minimum value found in the left striatum for PTC was observed 24-h post-injection and the decrease was of –8%, a value lower than that found in the ipsilateral side. No significant differences were found when the value obtained at 24 h was compared with that obtained at 48 h.
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CHAPTER 1
DISCUSSION As shown by the data here reported, the intrastriatal injection of 6-OHDA causes a continuous increase in the indices of oxidative stress in the ipsilateral side (striatum and ventral midbrain), which expands over 48 h for both lipid peroxidation and PCC, and over 24 h for PTC. This quick evolution of the indices of oxidative stress agrees with both morphological observations showing that DAergic neurons start to die within the first 24 h (Jonsson 1983, Ichitani et al. 1991, Jeon et al. 1995) and that rapid autoxidation of 6-OHDA takes place under physiological conditions (Soto-Otero et al. 2000, Méndez-Álvarez et al. 2001, Méndez-Álvarez et al. 2002). Once peak-values are reached, each of the indices begins a slow decline to values very close to those found in controls after 7-day post-injection. Taking into account the fact that the degeneration of the nigrostriatal system can last for 1–2 weeks (Sauer and Oertel 1994, Przedborski et al. 1995), our data appears to show that the here reported oxidative damage is the cause of the DAergic lesion and not a consequence of this process, but this is still open to question (Andersen 2004). Furthermore, the fact that the neurodegenerative process continues when the indices of oxidative stress returned to the initial values (control values) appears to prove that the oxidative stress generated by 6-OHDA autoxidation causes irreversible damage in DAergic neurons and endangers their survival. Similar findings of early oxidative stress have been observed after MPTP application (Przedborski et al. 2004) as well as after chronic treatment of rats with rotenone (Giasson et al. 2000). However, the fact that in our study the indices of oxidative stress increase simultaneously in both striatum and ventral midbrain seems to discard previous suggestions involving a chemical axotomic action of 6-OHDA in the delay and gradual degeneration of DAergic neurons found in this model of DAergic neurodegeneration (Sauer and Oertel 1994). At this point, it is interesting to note that the maximum increase in the indices of oxidative stress is higher in the ventral midbrain than in the striatum and occurs simultaneously. Assuming the accepted involvement of oxidative stress in apoptosis (Giasson et al. 2000), the apoptotic-like features observed 1–3 weeks after lesion (Marti et al. 1997), and the ability shown by caspase inhibitors to protect
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CHAPTER 1
against degeneration (Trojanowski and Lee 2003), our results corroborate the involvement of the oxidative stress caused by 6-OHDA autoxidation as a triggering factor in the development of neurodegeneration. In view of both the recently reported ability of oxidative stress to act as a primary event for α-synuclein polimerization and the involvement of these aggregates in neurodegenerative processes (Cutillas et al. 1999, Krantic et al. 2005), the fibrillization of α-synuclein could also be responsible for the slow rate of neurodegeneration observed after unilateral, intrastriatal administration of 6-OHDA. Evidently, both our results and the suggested hypothesis do not discard the suggested involvement of microglia in the corresponding neuronal death (Rodrigues et al. 2001, Przedborski and Goldman 2004), because the formation of certain uncharged ROS during the 6-OHDA autoxidation, with a relatively non short half-life, makes these substances highly diffusible through biological membranes and suitable for cellular signaling (Vroegop et al. 1995, Kamsler and Segal 2004). It is also important to emphasize that the unilateral injection of 6-OHDA also caused a significant increase in the indices of oxidative stress of the contralateral side, affecting both the striatum and the ventral midbrain. Our results show that the magnitude of these increases was lower than that found in the ipsilateral side, which agree with the reported inability of intrastriatal and unilateral injections of 6-OHDA to cause loss of cell bodies in the contralateral side (Lee et al. 1996). However, these data clearly preclude the use of the contralateral side as a control to assess neurochemical changes induced by 6-OHDA in this experimental model of PD. This may be explained by the above-mentioned ability of certain ROS generated by 6-OHDA autoxidation to diffuse through biological membranes. In summary, our data confirm that intrastriatal and unilateral injections of 6OHDA cause oxidative stress (lipid peroxidation and protein oxidation), which increases during the first 2-day post-injection and returns to approximate control levels at the 17-day post-injection. This appears to be the triggering factor for the neurodegenerative process, and the retrograde neurodegeneration following the first week post-injection seems to be a consequence of the cell damage caused within the first days post-injection. Finally, when this model is used to assess new neuroprotective
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CHAPTER 1
strategies or to study the oxidative potential of a specific factor, the measurement of brain indices of oxidative stress (TBARS and the content of oxidized groups in proteins) should be performed at 48-h post-injection, which is when maximum values are obtained.
Acknowledgments This study was supported by Grant BFI2003-00493 from the Ministerio de Ciencia y Tecnología with the contribution of the European Regional Development Found (Madrid, Spain) and Grant PGIDIT03PXIB20804PR from the Xunta de Galicia (Santiago de Compostela, Spain). The authors are indebted to Dr. J. L. Otero-Cepeda for statistical analysis of the results.
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CHAPTER 1
Fig. 1 Changes in TBARS levels in the ipsilateral and contralateral side of both striatum (St) and ventral midbrain (VM) after stereotaxic, unilateral (right), intrastriatal injection of 6-OHDA (6 g in 5 l of sterile saline containing 0.2% ascorbic acid) to rats. Each point represents the mean ± SD from five animals (n = 5). Asterisks denote values significantly different from the corresponding control (LSD test; p < 0.05).
97
CHAPTER 1
Fig. 2 Changes in PCC in the ipsilateral and contralateral side of both striatum (St) and ventral midbrain (VM) after stereotaxic, unilateral (right), intrastriatal injection of 6OHDA (6 g in 5 l of sterile saline containing 0.2% ascorbic acid) to rats. Each point represents the mean ± SD from five animals (n = 5). Asterisks denote values significantly different from the corresponding control (LSD test; p < 0.05).
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CHAPTER 1
Fig. 3 Changes in PTC in the ipsilateral and contralateral side of both striatum (St) and ventral midbrain (VM) after stereotaxic, unilateral (right), intrastriatal injection of 6OHDA (6 g in 5 l of sterile saline containing 0.2% ascorbic acid) to rats. Each point represents the mean ± SD from five animals (n = 5). Asterisks denote values significantly different from the corresponding control (LSD test; p < 0.05).
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CHAPTER 2
CHAPTER 2
Analysis of brain regional distribution of aluminium in rats via oral and intraperitoneal administration Sofía Sánchez-Iglesias,* Ramón Soto-Otero,* Javier Iglesias-González,* M. Carmen Barciela-Alonso,† Pilar Bermejo-Barrera† and Estefanía Méndez-Álvarez* *Laboratory of Neurochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain †Department of Analytical Chemistry, Nutrition and Bromatology, Faculty of Chemistry, University of Santiago de Compostela, Santiago de Compostela, Spain
J. Trace Elem. Med. Biol. (2007) 21, S1, 31–34.
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CHAPTER 2
ABSTRACT In the present work, accumulation and distribution of aluminium in the rat brain following both intraperitoneal and oral administration were studied. Male SpragueDawley rats received a daily i.p. injection of aluminium chloride (10 mg Al3+/kg/day) for one week or oral and progressively increasing administration of aluminium chloride and citric acid up to 100 and 356 mg/kg/day, respectively. Electrothermal atomic absorption spectrometry was used to determine aluminium concentration in different brain areas (cerebellum, ventral midbrain, cortex, hippocampus, and striatum). The results we obtained provided us insights about the most efficiency way for aluminium administration in neurochemical studies focused to investigate the ability of this metal to induce brain oxidative stress and consequently to cause neurodegeneration. Most of the brain areas showed accumulation of aluminium, but a greater and more significant increase was noted in the group receiving aluminium via intraperitoneal administration. Aluminium distribution was also dependent on the administration route. According to the here reported results, the intraperitoneal administration of aluminium was most effective in improving aluminium accumulation in the different areas of the rat brain. Our data suggest that aluminium neurotoxicity may be mediated by its particular distribution in specific brain areas.
Keywords: Aluminium, brain distribution, intraperitoneal, oral, rat.
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INTRODUCTION Aluminium is one of the most abundant metals in the earth‟s crust and all around present in our domestic environment. Although, it is considered a non-essential element for living organisms, the medical interest in this metal comes from the reported neurotoxicity of aluminium (Yokel 2000). The bioavailabilility of aluminium, its ability to cross the BBB, and the relatively slow rate of elimination from the brain, contribute to guarantee the accumulation of aluminium into the brain (Priest 2004), which represents an enhanced neurotoxicological risk. Thus, aluminium has been implicated in aging-related changes (Deloncle et al. 2001) and several neurodegenerative diseases (Kawahara 2005). Although, it is generally accepted that the neurotoxicity of aluminium is caused by its ability to increase oxidative damage in the brain (Moumen et al. 2001), the molecular mechanisms by which it causes neuronal damage are not fully understood (Zatta et al. 2002). Evidently, the non-redox nature of this metal, so as the extensive range of values reported in the literature concerning its accumulation in the brain, contribute greatly to this uncertain situation. The purpose of this study was to elucidate the precise localization of the absorbed aluminium in the brain following the use of two different administration routes, oral and intraperitoneal, in order to clarify its distribution in the brain and in this way contribute to understand all the factors involved in its neurotoxicity.
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MATERIALS AND METHODS Chemicals Nitric acid 69% Hiperpur from Panreac SA (Barcelona, Spain) was used to perform microwave digestions. H2O2 30% Suprapur and a dogfish muscle DORM-2 certified reference material were purchased from Merck (Darmstadt, FRG) and from the National Research Council (Otawa, Canada), respectively. Argon N50 (99.999% purity) was used as a sheath gas for the atomizer and to purge internally. Aluminium chloride hexahydrate was purchased from Sigma Chemical Co. (St. Louis, MO, USA). The water used for the preparations of solutions was of 18.2 M (Milli-RiOs/Q-A10 grade, Millipore Corp., Bedford, MA, USA). All remaining chemicals used were of analytical grade and were purchased from Fluka Chemie AG (Buchs, Switzerland).
Animal treatment Forty male Sprague-Dawley rats (200-250 g) were used in this study. All experiments were performed in accordance with the NIH publication “Principles of laboratory animal care” and approved by the Ethics Committee of the University of Santiago de Compostela. Animals were randomly divided into four experimental group: the first group was daily i.p. injected with aluminium chloride (Sigma Chemical Co.) in saline (0.9% NaCl) at a dose of 10 mg aluminium/kg/day (pH 4) for one week. The second group was i.p. injected with saline over the same period. The third group was given orally 25 mg aluminium/kg/day and 89 mg citric acid/kg/day in saline for one week. After this period, aluminium and citric acid doses were increased to 50 mg/kg/day and 178 mg/kg/day, respectively, for one more week. Finally, doses were adjusted to 100 mg aluminium/kg/day and 356 mg citric acid/kg/day for two additional weeks. Citric acid was added to enhance the gastrointestinal absorption of aluminium (Gómez et al. 1999). The fourth group was given saline orally during the entire
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experimental period of four weeks. Aluminium dosage was adjusted according to the animal‟s body weight just before experiment. All rats received a standard diet (A04, Panlab, Barcelona, Spain) and the corresponding drinking (saline or aluminium salt+citric acid) ad libitum. Body weight and fluid intake were measured three times a week to adjust the doses in order to achieve a constant aluminium and citric acid intake.
Brain samples After treatment, animals were sacrificed by decapitation and brains quickly excised. Regional brain segments [cerebellum (CE), ventral midbrain (VM), cortex (CO), hippocampus (H), striatum (ST)] were rapidly dissected out on ice plate, according to Paxinos and Watson (2007). Weighed brain regions were stored at –40°C until trace element analysis.
Electrothermal atomic absorption spectrometry (ETAAS) The samples were homogenised and digested with nitric acid (HNO3) and H2O2, using microwave energy. A portion of 500 mg of sample was weighed into a digestion vessel and 2 mL of HNO3 were added. Afterwards, vessels were introduced into the microwave oven at 100 W during 12 min. Then, 1 mL of H2O2 was added into digestion vessel and introduced into the microwave oven during 10 min at 300 W. Subsequently, the sample was adjusted to its final volume (5 mL) by addition of ultrapure water. A portion of 20 µL of the digested sample was introduced into the graphite furnace tube for its analysis by ETAAS. Measurements were performed using an atomic absorption spectrometer Model 1100 B (Perkin-Elmer, Norwalk, CT, USA), equipped with an HGA-700 graphite furnace atomizer and AS-70 autosampler. A hollow cathode lamp operating at 25 mA, which provided a 309 nm line with a spectral bandwidth of 0.7 nm, was used. Deuterium background correction and pyrolytic graphite coated tubes with L´vov platforms were employed. All measurements made during this study used integrated absorbance with an integration time of 5 s. The mineralization and
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atomization used were 1,500 and 2,800 ºC respectively (Table 1). The volume injected was 20 µL. Each sample was digested by triplicate and measured by duplicate. Aluminium concentrations in samples were calculated using a standard addition method in an analytical range of 0-20 µg/L. The limit of detection was 0.12 µg/g. The accuracy of the method was investigated using the Reference Material DORM-2 with a certificated aluminium concentration of 10.9±1.7 µg/g, being the aluminium concentration obtained 11.4±2.2 µg/g. Reagents for aluminium determination were of the highest available purity in order to avoid any risk of sample contamination. All glassware was washed and kept in 10% (v/v) HNO3 for at least 48 hours and then rinsed with ultrapure water (Milli-RiOs/Q-A10).
Statistical analysis Results were expressed as the mean ± SD. Statistical differences were tested using one-way ANOVA followed by Bonferroni‟s test for multiple comparisons. The accepted level of statistical significance was p < 0.05. All statistical procedures were carried out using the Statgraphics Plus 5.0 statistical package (Manugistics, Rockville, MD, USA).
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RESULTS Aluminium
distribution
in
the
brain
after
oral
and
i.p.
administration As can be seen in Fig. 1, aluminium content in brain tissue was significantly increased in both aluminium-exposed groups (i.p. and oral) when compared to the corresponding control, except in VM of the i.p. aluminium-treated group. All brain regions of oral aluminium-treated animals showed significant increased levels of aluminium in relation to their controls: +69% CE, +200% VM, +116% CO, +66% H, +143% ST, with highest levels in the ventral midbrain>striatum>cortex, cerebellum and hippocampus. In orally-treated control animals, all areas showed a similar accumulation of aluminium. In i.p. aluminium-treated animals, aluminium content was significantly increased compared to the respective i.p. controls (+727% CE, +667% CO, +877% H and +294% ST). Notwithstanding, the level of aluminium in VM was significantly reduced compared to that of the control group (–83%). Aluminium in i.p. metal-treated animals seemed
to
accumulate
preferentially
in
the
following
cerebral
areas:
hippocampus>cortex>striatum>cerebellum>ventral midbrain. When comparing the two different methods of aluminium administration, we noted a greater and significant increase of aluminium in the i.p. aluminium-treated groups compared to the orally-treated group: +77% H, +73% CO, +51% CE and +39% ST. In turn, aluminium concentration in VM was significantly reduced (–1963%).
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DISCUSSION Aluminium enters the brain through the BBB. Previous studies suggest that there are carrier-mediated mechanisms that allow uptake of aluminium into the brain and efflux into blood (Yokel 2002b). It was also proposed that aluminium distribution depends on the animal species in question and the chemical form of aluminium administered (Baydar et al. 2003). The aim of the present work was to evaluate the brain regional accumulation of aluminium in rats following the administration of aluminium chloride through two distinct administration routes: intraperitoneal and oral. Oral administration of aluminium chloride for four weeks resulted in a significant increase in brain aluminium concentration in all the investigated brain areas. These results agree with previous studies reporting an increase of aluminium concentration in both whole brain (Sahin et al. 1994) and specific areas of the brain (Gupta and Shukla 1995, Roig et al. 2006), which contribute to explain the impairment in motor coordination observed by some authors (Sahin et al. 1995). However, it has also been reported no significant accumulation of aluminium in the whole brain (Gómez et al. 1999, Colomina et al. 2002) and even a paradoxical reduction of aluminium concentration in the whole brain of mice chronically treated with a diet containing aluminium (Golub et al. 2000). This wide variety of results could be related with the aluminium salt used and/or the extent of brain area selected. Our results show that i.p aluminium chloride exposure for one week also caused a significant and greater aluminium accumulation in cerebellum, cortex, hippocampus and striatum, a finding that is consistent with previous literature concerning particular brain areas (Julka and Gill 1996a, Nayak and Chatterjee 2003, Abubakar et al. 2004b, Sakamoto et al. 2004). However, most of these publications used extensive cerebral regions. It has been also reported a no significant aluminium accumulation following i.p. administration of aluminium chloride (Moumen et al. 2001). The observation that i.p. administration of aluminium predominantly accumulates in the hippocampus is in accordance with a previous work (Julka and Gill 1996a). Our present study make the interesting point that, while oral administration of aluminium chloride resulted in a 111
CHAPTER 2
significant increase of the metal concentration in the ventral midbrain, i.p. administration led to a decrease in aluminium concentration in this cerebral region. In our opinion, this curious observation could be related to the specific composition of this area and the reported ability of aluminium to change the permeability of plasma membranes in function of their particular composition (Silva et al. 2002). Our results clearly show that aluminium accumulation in the brain not only varied with the administration route used but also in its distribution in the distinct brain areas. Evidently, both the presence of citric acid in the oral dose of aluminium and the difference in the time of treatment also could contribute to the reported differences. However, in view of the reported variance in aluminium distribution in different cerebral regions following both treatments, it can be argued that the effects of aluminium cannot be generalized to the whole brain and a study of the kinetics of aluminium distribution in specific cerebral areas is necessary to understand the neurotoxicity of this metal and its contribution to a particular neurological disorder.
Acknowledgments This study was supported by the Xunta de Galicia (Santiago, Spain; Grant PGIDIT03PXIB20804PR).
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Table 1. Graphite furnace programme for aluminium determination by ETAAS
Step Dry Pyrolisis Atomization Cleaning
Temperature (ºC) 150 1500 2800 2200
Ramp (s) 15 15 0 1
Hold (s) 20 20 5 5
Ar flow (mL min-1) 300 300 50 (read) 300
Fig. 1 Levels of aluminium in the different areas of the rat brain. Data are expressed as mean ± SD. Asterisks denote values significantly different (one-way ANOVA followed by a Bonferroni‟s test) for treatment versus control group (*, p < 0.01, **, p < 0.001) and for the oral-treated group versus intraperitoneally-treated group (***, p < 0.001).
20 Control
**
Al-treated
**
g Al
3+
/g
15
10
**
**
*** ** *** **
*** *
5
*** **
*** *
*
0 i.p.
oral CE
i.p.
oral VM
i.p.
oral CO
i.p.
oral H
i.p.
oral ST
113
CHAPTER 3
CHAPTER 3
Brain oxidative stress and selective behaviour of aluminium in specific areas of rat brain: potential effects in a 6-OHDA-induced model of Parkinson’s disease Sofía Sánchez-Iglesias,* Estefanía Méndez-Álvarez,*,§ Javier IglesiasGonzález,* Ana Muñoz-Patiño,†,§ Inés Sánchez-Sellero,‡ José Luís Labandeira-García,†,§ and Ramón Soto-Otero,*,§ *Laboratory of Neurochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain †Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain ‡Department of Pathological Anatomy and Forensic Sciences, Faculty of Veterinary Medicine, University of Santiago de Compostela, Lugo, Spain §Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain
J. Neurochem. (2009) 109, 879–888.
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ABSTRACT The ability of aluminium to affect the oxidant status of specific areas of the brain (cerebellum, ventral midbrain, cortex, hippocampus, striatum) was investigated in male Sprague-Dawley rats intraperitoneally treated with aluminium chloride (10 mg Al3+/kg/day) for ten days. The potential of aluminium to act as an etiological factor in PD was assessed by studying its ability to increase oxidative stress in ventral midbrain and striatum and the striatal DAergic neurodegeneration induced by 6-OHDA administered intraventricularly in an experimental model of PD. The results showed that aluminium caused an increase in oxidative stress (TBARS, PCC, and PTC) for most of the brain regions studied, which was accompanied by a decrease in the activity of some antioxidant enzymes (SOD, CAT, GPx). However, studies in vitro confirmed the inability of aluminium to affect the activity of those enzymes. The reported effects exhibited a regional-selective behaviour for all the cerebral structures studied. Aluminium also enhanced the ability of 6-OHDA to cause oxidative stress and neurodegeneration in the DAergic system, which confirms its potential as a risk factor in the development of PD.
Keywords: 6-hydroxydopamine, aluminium, antioxidant enzymes, lipid peroxidation, Parkinson‟s disease, protein oxidation.
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INTRODUCTION The human organism is constantly and inevitably exposed to aluminium, a ubiquitous metal which is the third most abundant element in the Earth‟s crust, representing 8% of total components (Martin 1997). Although, no biological function has yet been attributed to it (Yokel 2002a), aluminium is a toxicant implicated in dialysis encephalopathy (Alfrey et al. 1976), osteomalacia (Parkinson et al. 1979), noniron responsible anemia (Elliot et al. 1978), and also linked to many other diseases including AD (Exley 1999, Gupta et al. 2005), PD (Yasui et al. 1992), and amyotrophic lateral sclerosis (Kurland 1988). Its ubiquity and extensive use in products and processes coupled with its ability to cause neurodegeneration have made aluminium a cause of health concern (Exley 1999, Yokel 2000, Zatta et al. 2003). The daily reported mean dietary intake of 3.5 mg may be increased by the frequent use of aluminium-containing antiperspirants and nonprescription drugs (Weburg and Berstad 1986, Flarend et al. 2001), as well as by occupational exposure (Meyer-Baron et al. 2007). Aluminium entry into the brain occurs mainly through the BBB. Although the mechanism(s) responsible for aluminium transport at the BBB remains unclear, it has been reported that aluminium can penetrate into the brain as a complex with transferrin by a receptor-mediated endocytosis (Roskams and Connor 1990) and bound to citrate via a specific transporter, the system Xc (L-glutamate/L-CySH exchanger) is the most recently accepted candidate (Nagasawa et al. 2005). The apparently long half-life of aluminium in brain tissue has been used to explain its easy accumulation in the brain (Yokel et al. 2001b, SánchezIglesias et al. 2007b), which together with the long life of neurons could be related to the elevated levels of aluminium found in the brain of some patients suffering PD (Yasui et al. 1992) and AD (Perl and Brody 1980). However this fact should not be interpreted as the primary cause of those disorders. Nevertheless, and despite all hitherto reported data concerning aluminium neurotoxicity, the precise molecular mechanisms responsible for its neurotoxicity remain largely unknown. Even though it is not a transition metal, and consequently does 120
CHAPTER 3
not undergo redox reactions, numerous publications have detailed an increase in the formation of ROS after aluminium exposure (Nehru and Anand 2005). Most of the studies performed both in vitro and in vivo have attributed its neurotoxicity to the lipid peroxidation caused by the interaction between ROS and cell membranes (Gutteridge et al. 1985, Zatta et al. 2002), thus considering the latter as the main targets of the oxidantmediated damage. Furthermore, aluminium appears to affect the brain activities of several antioxidant enzymes (Julka and Gill 1996a). In addition, its ability to affect the expression of DA receptors D1 and D2 (Kim et al. 2007) as well as the functionality of mitochondria (Niu et al. 2005) has also been documented. However, the controversy surrounding these findings is such that both pro-oxidant (Zatta et al. 2002, Exley 2004a) and antioxidant (Oteiza et al. 1993a, Abubakar et al. 2004a) properties have been attributed to this metal. The usefulness of the studies to clarify the accepted involvement of aluminium in the pathogenesis of some neurodegenerative process has also been brought into question (Savory and Ghribi 2007). Consequently, the aim of this present study was to investigate the in vivo effects induced by aluminium on indices of oxidative stress in the cerebellum, ventral midbrain, cortex, hippocampus, and striatum of rat brain. We quantified the levels of lipid peroxidation (thiobarbituric acid reactive substances, TBARS) and the oxidant status of proteins (PCC, PTC), as well as an in vivo assessment of the effects of aluminium on the activity of certain antioxidant defence enzymes, which included SOD, GPx, and CAT. To shed some light on the molecular mechanisms involved, the effects of aluminium on the in vitro activity of antioxidant enzymes have also been investigated. Finally, taking into account the high levels of aluminium found in the SN of some patients suffering PD (Yasui et al. 1992), we investigated its ability to modify the capacity of 6-OHDA administered intraventricularly in an experimental model of PD (Soto-Otero et al. 2002, Sánchez-Iglesias et al. 2007a) to cause oxidative stress in ventral midbrain and striatum and to induce neurodegeneration in striatal DAergic terminals.
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CHAPTER 3
MATERIALS AND METHODS Chemicals Aluminium chloride hexahydrate, BSA, CAT, cytochrome c, desipramine hydrochoride, 3,3‟-diaminobenzidine, 2,4-dinitrophenylhydrazine hydrochloride, 5,5‟dithiobis-(2-nitrobenzoic acid), EDTA, GPx, GR, H2O2, ketamine/xylazine, mouse monoclonal antibody to TH, TBA, xanthine, and xanthine oxidase were purchased from Sigma Chemical Co. (St. Louis, MO, USA). Avidin-biotin-peroxidase complex and biotinylated secondary antibody were purchased from Vector (Burlingame, CA, USA). The water used for the preparations of solutions was Milli-RiOs/Q-A10 grade, (Millipore Corp., Bedford, MA, USA). All remaining chemicals used were of analytical grade and were purchased from Fluka Chemie AG (Buchs, Switzerland).
Animal treatment Adult male Sprague-Dawley rats (200-250 g) were used to perform the in vivo studies. All animals were housed individually in polypropylene cages to reduce extraneous trace element contamination in a room equipped with 12 h light/dark automatic light cycles, maintained at 221°C with a relative humidity of 65%. All experiments were carried out in accordance with the “Principles of laboratory animal care” (NIH publication No. 86-23, revised 1996) and approved by the corresponding committee at the University of Santiago de Compostela. Aluminium dosage was adjusted according to animal‟s body weight just before each experiment. All rats were allowed a standard maintenance diet (A04, Panlab S.L., Barcelona, Spain) and water ad libitum. Animals were randomly assigned to two experimental groups. The first group was subdivided into two subgroups, each consisting of ten animals: rats in subgroup A were daily i.p. injected with aluminium chloride in saline (NaCl 0.9%) at a dose of 10 mg Al3+/kg for 10 days; rats in subgroup B were injected with the same volume of
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saline over the same period. The second group was subdivided into four subgroups of 11 animals each: rats in subgroup C were used as normal (i.e. non-lesioned) controls, and received the corresponding injections of vehicle for 10 days; rats in subgroup D were i.p. injected with aluminium chloride at a dose of 10 mg Al3+/kg/day for 10 consecutive days; rats in subgroup E received i.p. injections of saline for 10 days and were lesioned on the 8th day (two hours after i.p. injection) with 200 µg 6-OHDA in 3 µl sterile saline containing 0.2% ascorbic acid injected in the third ventricle; rats in subgroup F were i.p. injected with aluminium chloride (10 mg Al3+/kg/day) for 10 days and were lesioned with 6-OHDA in the same way as subgroup E. Injection solutions containing aluminium were prepared by dissolving aluminium chloride in saline, adjusting to pH 4.6 with sodium hydroxide, and waiting the equilibration time necessary to obtain a clear solution. In all cases the volume injected was 0.5 ml. Stereotaxic coordinates for intraventricular injection of 6-OHDA were 0.8 mm posterior to bregma, midline, 6.5 mm ventral to the dura, and tooth bar at 0. The solution was injected with a 10 µl Hamilton syringe coupled to a motorized injector (Stoelting, Wood Dale, IL, USA), at 0.5 µl/min, and the cannula was left in situ for 5 min after injection. All surgery was performed under ketamine/xylazine anesthesia, and 30 min prior to injection of 6-OHDA, rats received desipramine (25 mg/kg i.p.) to prevent uptake of 6-OHDA by noradrenergic terminals. The accuracy of the lesions and cannula placement were confirmed by post-mortem analysis with cresyl violet staining.
Brain samples At the end of the experimental period animals of subgroups A and B were stunned with carbon dioxide and sacrificed by decapitation. Brains were quickly removed and rinsed with ice-cold saline. Regional brain segments (cerebellum, ventral midbrain, cortex, hippocampus, striatum) according to Paxinos and Watson (2007) were immediately dissected out on an ice plate. For biochemical assays, weighed brain samples were individually homogenized in a Na2PO4/KH2PO4 buffer (pH 7.4) isotonized with KCl (1:6 w/v for cerebellum, 1:2 for cortex; 1:30 for ventral midbrain;
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CHAPTER 3
1:15 for hippocampus and 1:10 for striatum) in a Dounce tissue grinder (Kontes, Vineland, NJ, USA). The homogenates were then centrifuged at 14,000 g for 20 minutes at 4°C. The supernatants were aliquoted and stored at –80°C to determine protein content and the activity of GPx, SOD, and CAT. The resulting pellets were resuspended with cold Na2PO4/KH2PO4 buffer (pH 7.4) isotonized with KCl and containing 20 M BHT and 20 M desferrioxamine. These compounds were used to prevent amplification of lipid peroxidation during the progression of the analysis. Then, homogenates were immediately sonicated for 5 seconds (250 Digital Sonifer, Branson Ultrasonic Co., Danbury, CT, USA). These samples were used for the quantification of TBARS, PCC, PTC, and protein concentration. Forty-eight hours after lesion with 6-OHDA, five rats of subgroups C, D, E, and F were killed according to the above cited procedure in order to perform biochemical studies because it has been previously reported that the peak for oxidative stress is reached at this time (Sánchez-Iglesias et al. 2007a). In these rats, the levels of the oxidative stress caused by 6-OHDA were estimated by quantification of both lipid peroxidation and protein oxidation in ventral midbrain and striatum.
Preparation of brain mitochondria Brain mitochondria from Sprague-Dawley rats weighing 200-250 g were obtained by differential centrifugation according to a previously published method (Méndez-Álvarez et al. 1997) and protein concentration determined according to Markwell et al. (1978), using BSA as the standard.
Determination of TBARS, PCC, and PTC The TBARS, PCC, and PTC determinations for in vitro and in vivo experiments were performed spectrophotometrically as previously described in Hermida-Ameijeiras et
al.
(2004)
and
Sánchez-Iglesias
et
al.
(2007a),
respectively.
2,4-
Dinitrophenylhydrazine hydrochloride and 5,5‟-dithiobis-(2-nitrobenzoic acid) were
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CHAPTER 3
used as chemical dosimeters for PCC and PTC determinations, respectively. For in vitro experiments, AlCl3 was preincubated with brain mitochondria at a final Al3+ concentration of 5 M.
Measurement of SOD activity SOD activity was spectrophotometrically determined by the method reported by McCord and Fridovich (1969). The assay was performed at 25°C in 2.8 ml of 50 mM potassium phosphate buffer (pH 7.8) containing 0.1 mM EDTA, 0.05 mM xanthine and 0.01 mM cytochrome c. Then, 100 l xanthine oxidase (0.02 U) were added in order to produce a rate of reduction of cytochrome c of 0.025 absorbance unit per minute, followed by 100 l of brain sample. Increase in absorption was monitored at 550 nm for 5 minutes. SOD activity was expressed in U/mg protein. To evaluate the potential in vitro effect of aluminium on SOD, different concentrations of Al3+ (10, 50, 100 M) were added, followed by 100 l of SOD (1 U) instead of brain sample.
Measurement of GPx activity GPx activity was spectrophotometrically measured by a modified version of the method reported by Flohe and Gunzler (1984). Briefly, the reaction mixture consisted of 500 l phosphate buffer (60 mM, 0.6 mM EDTA, 1 mM NaN3, pH 7.0), 100 l GR (0.5 U), and 100 l GSH (1 mM). Brain sample (100 l) was added to the reaction mixture and preincubated at 37°C for 10 min. Then, 100 l NADPH (150 μM in 0.1% NaHCO3) were added to reaction mixture and the hydroperoxide-independent consumption of NADPH monitored for 3 min. The reaction was started by adding 100 l H2O2 (150 μM) and the decrease in absorption at 340 nm monitored for 5 min. Molar extinction coefficient of 6.22·103 M-1·cm-1 of NADPH at 340 nm was used to calculate GPx activity which was expressed in mU/mg protein. When assessing the in vitro effect of aluminium on GPx activity, different concentrations of Al3+ (10, 50, 100 M) were
125
CHAPTER 3
initially incorporated to the reaction mixture, followed by 100 l of GPx (0.2 U) instead of brain sample.
Measurement of CAT activity CAT activity was polarographically measured following the formation of O2 using a Clark-type oxygen electrode, according to a slight modification to a previous published method (Méndez-Álvarez et al. 1998). Briefly, 100 l brain sample were incubated in the electrode chamber and the reaction started with the addition of 20 l of a 500 M solution of H2O2. CAT activity was expressed as U/mg protein. For in vitro studies, 100 l of CAT (20 U) were first added to the reaction mixture, followed by different concentrations of Al3+ (10, 50, 100 M) in order to estimate the effect of the metal on CAT activity.
Determination of MAO activity MAO
activity
was
spectrophotometrically
measured
in
mitochondria
preparations as previously described (Soto-Otero et al. 2001), using kynuramine as a non-selective substrate and (-)-deprenyl and clorgyline as irreversible inhibitors for MAO-A and MAO-B estimation, respectively. Different concentrations of Al3+ (10, 50, 100 M) were incorporated to the incubation in order to assess the effect of aluminium on both MAO-A and MAO-B activity.
Immunohistochemistry The remaining six rats of subgroups C, D, E, and F were processed for immunohistochemistry. Animals were killed by a chloral hydrate overdose one week post-lesion and then processed for TH immunohistochemistry according to a previously published methodology (Rey et al. 2007).
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CHAPTER 3
Statistical analysis Data were expressed as the mean ± SD. Statistical differences were tested using oneway ANOVA followed by Bonferroni‟s test for multiple comparisons and by post hoc Student-Newman-Keuls test for immunohistochemistry studies. The statistical significance was set at p < 0.05. Normality of populations and homogeneity of variances were verified before each ANOVA. All statistical procedures were carried out using the Statgraphics Plus 5.0 statistical package (Manugistics, Rockville, MD, USA).
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CHAPTER 3
RESULTS In vivo effects of aluminium administration on brain lipid peroxidation and protein oxidation Lipid peroxidation was assessed by the determination of TBARS concentration, and protein oxidation was estimated by both PCC and PTC. As shown in Fig. 1A, animals exposed to aluminium (10 mg Al3+/kg/day for 10 days) exhibited a significant increase in lipid peroxidation in the regions of cerebellum (+159%), ventral midbrain (+54%), cortex (+20%) and striatum (+33%), while there were no significant changes in hippocampus. TBARS levels in the striatum were particularly high when compared with those found in other cerebral regions and in both aluminium-treated and control rats. Following aluminium treatment, both PCC (Fig. 1B) and PTC (Fig. 1C) were significantly elevated as compared to controls in cerebellum (+26%, +19%, respectively), ventral midbrain (+135%, +15%, respectively) and striatum (+26%, +16%, respectively), while there was a significant decrease in the cortex region (–12%, –16%, respectively) and in the hippocampus (–20%, –26%, respectively). When compared to other areas of non treated animals, PCC and PTC control levels were significantly higher in cerebral cortex and lower in the ventral midbrain (Figs. 1B and 1C).
In vivo effects of aluminium administration on the brain activity of different antioxidant enzymes The effects of aluminium administration (10 mg Al3+/kg/day for 10 days) on the activity of different antioxidant enzymes (SOD, GPx, CAT) were also studied in several brain regions, and the results showed that the i.p. administration of aluminium influenced SOD activity (Fig. 2A). Thus, there was a significant decrease in cerebellum (–26%) and cortex (–21%) of the aluminium-treated group, while a significant increase
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was noted in hippocampus (+22%). No significant changes were detected in ventral midbrain and striatum as compared with the controls. As depicted in Fig. 2B, exposure to aluminium caused depletion in the activity of GPx in cerebellum (–26%), ventral midbrain (–28%), cortex (–28%), and striatum (–11%). By contrast, GPx activity increased in the hippocampus (+40%). Exposure of rats to aluminium decreased the levels of CAT activity (Fig. 2C) in the cerebellum (–41%), ventral midbrain (–29%), and striatum (–25%) compared to respective controls. CAT activity was not significantly modified in the cortex, but showed a significant increase in the hippocampus (+35%).
Effects of aluminium administration on the degeneration of DA terminals in the striatum In control rats, i.e. rats not lesioned with 6-OHDA (subgroup C) and rats treated with aluminium alone (subgroup D), the DAergic neurons in the pars compacta of the SN were intensely immunoreactive to TH, and a dense and evenly distributed TH immunoreactivity (TH-ir) was observed throughout the striatum, which indicated the presence of a dense network of nigrostriatal DAergic terminals (Fig. 3A-B). No significant changes in the density of DA striatal terminals were observed in control rats (i.e. not injected with 6-OHDA; subgroups C and D; Fig. 4). TH-ir terminal density was higher in the control groups (subgroups C and D; Fig. 3A-B) than in rats that were intraventricularly injected with 6-OHDA (subgroups E and F; Fig. 3C-D). We observed a significant decrease in TH-ir terminal density (–27%) in rats intraventricularly injected with 6-OHDA when compared to control rats (subgroup-C rats). In rats i.p. treated with aluminium and subjected to intraventricular injection of 6-OHDA (subgroup F), the reduction in the density of DA striatal terminals with respect to the control rats (subgroup D) and rats injected with 6-OHDA (subgroup E) was statistically significant (–48% and –28%, respectively; Fig. 4).
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Effects of aluminium administration on brain lipid peroxidation and protein oxidation in 6-OHDA-lesioned rats and controls Once again, the concentration of TBARS was used as an index of lipid peroxidation in striatum and ventral midbrain (Fig. 5A). Both regions of animals i.p. injected with aluminium alone (subgroup D) showed a statistical difference in TBARS production compared to non-lesioned (subgroup C) control rats (+40% in ventral midbrain and +16% in striatum). Intraventricular injection of 6-OHDA resulted in a significant increase in TBARS concentration in both striatum and ventral midbrain when compared to control rats (+29% and +76%, respectively) and to animals treated with aluminium (+12% and +26%, respectively)). Ventral midbrain and striatum TBARS levels in rats i.p. treated with aluminium and intraventricularly injected with 6OHDA were +107% and +40% (respectively) increased in respect to control animals. When compared to rats only treated with aluminium (i.e. without 6-OHDA; subgroup D), the TBARS levels of subgroup-F rats were markedly increased in both regions (+47% in ventral midbrain and +21% in striatum) and there were also significant differences when compared with subgroup E, rats only lesioned with 6-OHDA (+17% in ventral midbrain and +8% in striatum). Protein oxidation was assessed by the determination of PCC and PTC in the samples of striatum and ventral midbrain. No significant changes were noticed in the PTC (Fig. 5C) except for rats lesioned with 6OHDA when compared with animals treated only with aluminium (–11%). By contrast, as shown in Fig. 5B, intraventricular injection of 6-OHDA induced a significant increase in the PCC in striatum and ventral midbrain (+33% and +22%, respectively) as compared with control rats. Treatment with aluminium (subgroups D) revealed a significant difference in ventral midbrain and striatum as compared to control rats (+11% and +18%, respectively). On the other hand, in subgroup F (animals treated with aluminium and lesioned with 6-OHDA) the PCC was reduced in both regions (–16% in ventral midbrain and striatum) as compared to the rats lesioned with 6-OHDA.
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In vitro effects of aluminium on the lipid peroxidation and protein oxidation induced by 6-OHDA autoxidation in brain mitochondrial preparations As depicted in Fig. 6A, the incubation of 6-OHDA (10 M) with brain mitochondria at 37°C for 20 min induced a significant production of TBARS when compared to the mitochondria (Mit) and Mit+Al controls (+91% and +116%, respectively). Significant changes in TBARS production (+100%, +127%) were observed when the autoxidation of 6-OHDA occurred in the presence of Al3+ (5 M) as compared to the Mit and Mit+Al controls, respectively. However, the presence of aluminium did not significantly affect the level of TBARS found after the incubation of 6-OHDA in mitochondrial preparations when compared to the Mit+6-OHDA control. The incubation of 6-OHDA (10 M) with brain mitochondria at 37°C for 20 min induced a significant increase in the PCC (+7%; Fig. 6B) as compared to the Mit control. However, the results obtained in the presence of Al3+ (5 M) were not significantly different from control values. As can be seen in Fig. 6C, the PTC exhibited a significant reduction (–9%) in the incubation of 6-OHDA (10 M) with brain mitochondria at 37°C for 20 min when compared with that obtained in the control with mitochondria alone and Mit+Al3. The presence of aluminium had no significant effect on the PTC found with mitochondrial incubations when compared to controls.
In vitro effects of aluminium on the enzyme activities of GPx, SOD, CAT, and MAO The results regarding the effect of aluminium on the in vitro activities of GPx, CAT, SOD, MAO-A and MAO-B enzymes are displayed in Table 1. In all cases, no significant differences were detected between assays performed in the presence and in the absence of Al3+ (10, 50, 100 M)
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DISCUSSION Aluminium is a non-redox metal whose accumulation in the brain has been linked to various neurodegenerative diseases (Yokel 2000, Zatta et al. 2003). Several hypotheses have been given to explain its reported ability to promote biological oxidations (Exley 2004a). Thus, it has been shown to facilitate iron-induced lipid peroxidation (Gutteridge et al. 1985); non-iron-induced lipid peroxidation (Verstraeten and Oteiza 2000); non-iron-mediated oxidation of NADH (Kong et al. 1992); and noniron-mediated formation of OH (Méndez-Álvarez et al. 2002). Additionally, it also appears to inhibit several antioxidant enzymes in different parts of the brain (Nehru and Anand 2005). In the present study aluminium was administered at a dosage regimen to guarantee its accumulation in different areas of rat brain (Sánchez-Iglesias et al. 2007b). Aluminium-treated animals remained healthy and showed no signs of toxicity during the treatment. However, certain tiny, white inclusions were observed floating in the abdominal cavity, probably caused by a partial precipitation of the aluminium and previously reported (Abubakar et al. 2004a). Previous studies have shown results ranging from no significant changes in TBARS levels (Oteiza et al. 1993b), to an increase in TBARS levels (Sharma and Mishra 2006), and a significant decrease in TBARS levels (Abubakar et al. 2004b). Our data clearly demonstrate that aluminium exposure caused a significant increase in the levels of TBARS in most of the brain areas studied, but particularly so in the cerebellum. Although, some authors have reported a decrease (Esparza et al. 2003) or no changes (Deloncle et al. 1999) in the levels of TBARS, our results are in total (Esparza et al. 2005, Nehru and Anand 2005, Dua and Gill 2001, Jyoti et al. 2007) or partial agreement (Julka and Gill 1996a) with most previously published data. Curiously, we found no significant changes in the levels of TBARS in the hippocampus following aluminium administration. In our opinion, the apparent contradictory results found in the literature are due to the use of different chemical forms for aluminium exposure (Esparza et al. 2003, Julka and Gill 1996a) and/or to the use of different 132
CHAPTER 3
administration routes (Deloncle et al. 1999, Jyoti and Sharma 2006) as we have demonstrated recently (Sánchez-Iglesias et al. 2007b). Another index to assess oxidative stress is the oxidant status of proteins. We found that the effects caused by aluminium on both PCC and PTC were not homogenous for all areas studied. Indeed, our data showed that aluminium provoked an increase in both PCC and PTC in the cerebellum, ventral midbrain, and striatum, whereas a decrease was found in the cortex and hippocampus. The most noteworthy effect of these results is the lack of correlation between the increase observed in the PCC, ostensibly a consequence of a situation of oxidative stress, and the apparently contradictory increase in PTC. The increase in the PTC may be a consequence of increased GSH production (Khanna and Nehru 2007) and its subsequent capacity to reduce disulfide groups in proteins. Our results contrast with previous findings that aluminium exposure affects neither PCC (Oteiza et al. 1993b) nor PTC (Oteiza et al. 1993b) in whole brain. Others report a significant increase of PCC in both hippocampus (Jyoti and Sharma 2006) and cortex (Jyoti et al. 2007) and a significant loss of PTC in whole brain (Dua and Gill 2001). Once again, this variability in relation to previous data appears to corroborate the importance of the chemical speciation of aluminium and the route of administration. Interestingly, the aluminium salt used not only affects the accumulation of this metal in different cells but also modulates its toxic effects (Lévesque et al. 2000). Despite these findings and taking into account the complexity of the aluminium speciation chemistry (Bharathi et al. 2008), it is very difficult to gain insight into the relation between the particular chemical speciation of aluminium in the brain and its biological effects. Nevertheless, our results clearly show that aluminium can create a situation of oxidative stress in most brain areas. This is mainly a consequence of the fact that aluminium is a strong Lewis acid which allows it to react with the superoxide anion and form a metal-superoxide complex (AlO2●2+), which is a more potent oxidant than the superoxide anion and putatively has a high catalytic potential, as suggested by Kong et al. (1992) and later discussed by Exley (2004a). These changes were accompanied by significant variations in the activity of SOD, GPx, and CAT. Our results indicate that all the neural tissues examined, except
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hippocampus, showed similar behaviour patterns and emphasize a significant decrease in the enzyme activity of most antioxidant systems, and agree with previous studies (Julka and Gill 1996a, Dua and Gill 2001, Abubakar et al. 2004a, Nehru and Anand 2005, Jyoti et al. 2007). Our in vitro experiments show no significant modification in the enzyme activity of either of SOD, GPx, and CAT, which we interpret as a declination of the gene expression of antioxidant enzymes (González-Muñoz et al. 2008).This reduction in antioxidant enzyme activity helps to explain the brain oxidative stress observed following aluminium administration. Furthermore, the reduction in GPx activity also explains the increase in the ratio GSH/GSSG previously reported by other authors (Esparza et al. 2003, Khanna and Nehru 2007), which helps explain the increase in the PTC found after aluminium exposure. The inability of aluminium to affect both MAO-A and MAO-B activity discards their involvement in the aluminium-induced brain oxidative stress. Data showing a partial disagreement with our findings have also been reported (Esparza et al. 2005), but is possibly due to the regimen of aluminium administration. A putative explanation for the increase in the activity of SOD, GPx, and CAT in the hippocampus (Sánchez-Iglesias et al. 2007b), may be the existence of a compensatory mechanism due to the ability of cells to increase the expression of antioxidant enzymes when exposed to high levels of toxicants (Gechev et al. 2002), an effect which could overcome the ability of moderate levels of aluminium to inhibit gen expression of antioxidant enzymes. Another interpretation could be the confinement of aluminium in granulovacuoles of neurofibrillar tangles due to its high capacity to interact with tau proteins in hippocampal cells (Walton 2006), thus reducing the presence of free aluminium and consequently its disposition to affect the activity of antioxidant enzymes and generate oxidative stress. Although, our findings contrast with those of Julka and Gill (1996a), similar results were also found by Esparza et al. (2003). We used an animal model of PD induced by 6-OHDA administration in the third ventricle to assess the ability of aluminium to affect both the index of oxidative stress in the nigrostriatal system and the extent of lesions of the DA system in the striatum. Our results showed that aluminium causes an enhancement in 6-OHDA-induced lipid peroxidation and protein oxidation (except for PTC in ventral midbrain). The administration of aluminium alone (i.e. without 6-OHDA) also caused a significant 134
CHAPTER 3
difference in the levels of both lipid peroxidation and protein oxidation for PCC. Although, these results are in partial agreement with the results obtained with nonlesioned rats, they do not agree with the in vitro results obtained using brain mitochondria preparations, in which we found no significant effect due to the presence of aluminium. Evidently, these findings corroborate the importance of the in vivo studies in this kind of investigation, which appears to be a consequence of the tight relationship existing among the different molecular mechanisms coexisting within the brain. Our immunochemical study showed that aluminium administration alone caused no significant change in TH-ir striatal terminals. In contrast, lesion with 6-OHDA caused a loss of TH-ir striatal terminals, which was significantly increased with the administration of aluminium. Obviously, these data show the ability of aluminium to increase the capacity of 6-OHDA to cause nigrostriatal neurodegeneration. Evidently, the importance of these data is increased by the ability of neuromelanin to bind aluminium which may be the cause of the high concentration of aluminium found in the brain of certain patients suffering PD (Yasui et al. 1992). Furthermore, our results also help us understand the reported ability of aluminium to potentiate etiological agents and accelerate the progression of a disease (Exley and Esiri 2006). In conclusion, aluminium acts mainly as a pro-oxidant probably by reducing the activity of defence antioxidant enzymes. In addition, the increase in oxidative stress together with enhanced 6-OHDAinduced neurodegeneration, suggest the participation of free radical-induced oxidative cell injury in mediating aluminium neurotoxicity. Interestingly, we demonstrated that aluminium neither enhanced lipid peroxidation nor decreased antioxidant enzyme activities in the hippocampus. Given that aluminium content was markedly increased in the hippocampus (Sánchez-Iglesias et al. 2007b), this dual effect could be related to the biphasic behaviour of aluminium previously reported by Abubakar et al. (2004a). In our opinion, the high concentration of aluminium in the hippocampus may possibly induce an increase in defence enzyme levels, which could cause the steady state of TBARS levels after aluminium exposure. However, in the remaining cerebral areas, antioxidant enzymes have a lower activity, which is interpreted as a consequence of the postulated oxidant potential of AlO2●2+ (Kong et al. 1992, Exley 2004a) and consequently the factor responsible for the oxidative impairment found in those brain areas. Finally, we
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assume that the distinct cerebral areas exhibit different sensitivities to aluminium, which can be partly explained by the differences in the brain barrier mechanisms. In fact, our data lean towards the concept of the blood-brain regional barrier introduced by Zheng et al. (2003). Evidently, the hypothesis that it would be more accurate to talk about a blood-hippocampal barrier and a blood-striatum barrier, for example, needs to be corroborated and characterised by future research.
Acknowledgments This study was supported by grants PGIDIT03PXIB20804PR (to R.S.-O.) and PGIDIT07CSA005208PR (to J.L.L.-G.) from XUGA (Santiago de Compostela, Spain), and grants SAF2007-66114 (to R.S.-O.) and BFU2006-07414 (to J.L.L.-G.) from Ministerio de Ciencia e Innovación (Madrid, Spain).
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Table 1. In vitro effects of the presence of aluminium on the enzyme activities of SOD, GPx, CAT, and MAO
MAO 3+
Al (M)
SOD (U)
GPx (U)
CAT (U)
control 10 50 100
10.8 0.86 11.2 0.78 11.3 0.41 11.0 0.92
1.96 0.194 2.14 0.131 2.25 0.115 2.17 0.257
24.7 1.77 22.8 0.42 23.4 1.43 24.0 2.75
(nmol 4-HQ/mg protein/min)
MAO-A 1.15 0.077 1.14 0.054 1.13 0.083 1.14 0.095
MAO-B 2.19 0.057 2.15 0.064 2.17 0.089 2.16 0.052
SOD, GPx, and CAT activities were determined using commercial enzymes, while MAO activity (MAO-A and MAO-B) was determined using mitochondrial preparation obtained from rat brain. All the incubations were performed at 37ºC. Abbreviations: SOD, superoxide dismutase; GPx, glutathione peroxidase; CAT, catalase; MAO, monoamine oxidase; 4-HQ, 4-hydroxyquinoline. Data are expressed as means SD from four determinations (n = 4). Significance of differences among groups was assessed by a one-way ANOVA followed by a Bonferroni‟s test. No significant differences were obtained for p < 0.05.
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Fig. 1 Levels of TBARS (A), protein carbonyls (B), and protein thiols (C) in different brain areas of rats i.p. treated with saline (control) or aluminium chloride (10 mg Al3+/kg/day) for ten days. Abbreviation: Al, aluminium. Data are expressed as means ± SD from five rats (n = 5). Significance of differences among groups was assessed by a one-way ANOVA followed by a Bonferroni‟s test. Asterisks denote values significantly different from the corresponding control (*, p < 0.05; **, p < 0.01; ***, p < 0.001).
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Fig. 2 Enzyme activity of: SOD (A), GPx (B), and CAT (C) in different brain areas of rats i.p. treated with saline (control) or aluminium chloride (10 mg Al3+/kg/day) for ten days. Abbreviation: Al, aluminium. Data are expressed as means ± SD from five rats (n = 5). Significance of differences among groups was assessed by a one-way ANOVA followed by a Bonferroni‟s test. Asterisks denote values significantly different from the corresponding control (*, p < 0.05; **, p < 0.01; ***, p < 0.001).
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Fig. 3 Microphotographs showing changes in the striatal TH-ir one week post-lesion in rats injected intraventricularly with vehicle (i.e. controls; A), i.p. treated with aluminium (10 mg Al3+/kg/day) for ten days (B), lesioned intraventricularly on the 8th day with 200 µg 6-OHDA (C), or i.p. treated with aluminium for 10 days and lesioned on the 8th day with 6-OHDA (D). Scale bar = 1 mm.
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Fig. 4 Density of striatal DAergic terminals estimated as optical density, one week postsurgery in the different experimental groups. Abbreviation: TH-ir, tyrosine hydroxylase immunoreactivity. Optical densities are expressed as percentages of the values obtained in the control groups. Data are expressed as means ± SD obtained from six animals (n = 6). Means that differ significantly are indicated by a different letter (p < 0.05, one-way ANOVA and post-hoc Student-Newman-Keuls test).
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Fig. 5 Levels of TBARS (A), protein carbonyls (B), and protein thiols (C) in both ventral midbrain and striatum of different groups of rats: control, i.p. treated with saline for 10 days and injected intraventricularly with saline; control+Al, i.p. treated with aluminium for 10 days and injected intraventricularly with saline; 6-OHDA, i.p. treated with saline for 10 days and lesioned with 6-OHDA on the 8th day; and finally 6OHDA+Al, i.p. treated with aluminium for 10 days and lesioned on the 8th day with 6OHDA. Doses used: aluminium (10 mg Al3+/kg/day), 6-OHDA (200 µg). Abbreviation: Al, aluminium. Rats were sacrificed two days after lesioning. Data are expressed as means ± SD from five rats (n = 5). Significance of differences among groups was assessed by a one-way ANOVA followed by a Bonferroni‟s test. Asterisks, pads and section sign denote values significantly different from the corresponding controls: control, control+Al, 6-OHDA respectively (*, #, §, p < 0.05; **, # #, §§, p < 0.01; *** p < 0.001).
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Fig. 6 In vitro effects of Al3+ (5 M) on TBARS formation (A), protein carbonyl content (B), and protein thiol content (C) induced by the autoxidation of 6-OHDA (10 M) in mitochondrial preparations (1 mg protein/ml) from rat brain. Mitochondria incubations were performed in phosphate buffer (pH 7.4, KCl isotonic) at 37°C for 20 min. Abbreviation: Al, aluminium. Data are expressed as means SD from five independent experiments. Significance of differences among groups was assessed by a one-way ANOVA followed by a Bonferroni‟s test. Asterisks, pads and section sign denote values significantly different from the corresponding controls: Mit, Mit+Al, and Mit+6-OHDA, respectively (*, #, p < 0.05; ***, # # #, p < 0.001).
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147
SUMMARY
SUMMARY
SUMMARY Aluminium has become an important health concern due to both the frequent exposure to this metal and the suggested ability of aluminium to cause neurodegeneration. Pathological conditions such as PD have been associated with the accumulation of aluminium in brain. Although, aluminium is not a redox metal, it has been reported to be able to enhance brain oxidative stress. However, the molecular mechanism of its neurotoxicity remains not well understood. Consequently, we resolved to gain insight into the mechanisms of aluminium neurotoxicity in oxidative stressinduced degenerative processes in relation with PD. Before starting the whole procedures with aluminium, it was crucial to establish the kinetics of the oxidative damage induced in a 6-OHDA model of PD and also to quantify the changes observed in the indices of lipid peroxidation and oxidant status of proteins in striatum and ventral midbrain. These results would thereafter enable us to decide at which exact post-injection time should be performed the measurement of indices of brain oxidative stress when assessing the oxidative effects of aluminium. To accomplish the first part of this thesis, we chose the unilateral and intrastriatal injection of 6-OHDA to lesion the DAergic nigrostriatal pathway system in male SpragueDawley rats. This procedure has been extensively used to examine the degeneration of the DAergic neurons characteristics of PD. When compared to others 6-OHDA models with injections into the SN or the nigrostriatal tract, this method mimics more closely the progression of PD as it leads to a slower retrograde degeneration of the nigrostriatal system over a period of several weeks (Sauer and Oertel 1994, Przedborski et al. 1995, Lee et al. 1996, Shimohama et al. 2003). In fact, this allowed us to use different groups of rats sacrificed at distinct post-injection times (from 5 min to 7 days). Our results clearly indicated that unilateral and intrastriatal injection of 6-OHDA results in increased levels of lipid peroxidation and protein oxidation in the ventral midbrain and in the striatum. We observed for both areas an aument during the first 2 days postinjection and values returned to near control levels at the 7 day post-injection. Peak
151
SUMMARY
values were attained at 48 hours post-injection for both TBARS and PCC, and at 24 hours for PTC. Interestingly, lower but significant increases in oxidative stress levels were also seen in the contralateral side (ventral midbrain and striatum) excluding this zone as a control to determine neurochemical alterations caused by 6-OHDA in this experimental model of PD. At last and according to the obtained results, we decided to establish the optimal time of 48 hours post-injection for quantification of brain oxidative stress indices when assessing the oxidative potential of aluminium in this experimental model of PD. The second part of this thesis consisted in developing a dosage regimen of aluminium to rats which would guarantee a significant accumulation of this metal in brain areas and also to determine its precise distribution in the brain. As it was previously suggested that aluminium distribution depends on the animal species in question and the chemical form of aluminium administered, we opted for two distinct administration routes: oral and intraperitoneal. Sprague-Dawley rats were either daily i.p. injected with aluminium chloride (10 mg Al3+/kg/day) for 1 week, or given orally progressive increasing doses of aluminium chloride (25, 50, 100 mg Al3+/kg/day) supplemented with citrate (89, 178, 356 mg/kg/day) during 4 weeks. Our results showed that both administration routes led to aluminium accumulation. A greater and more significant increase was noted in the group receiving aluminium via intraperitoneal administration for most brain areas except in ventral midbrain. Distribution also varied with the administration route used. In accordance to these results we resolved to use the intraperitoneal administration route to clarify the brain oxidative stress provoked by aluminium. Finally the third phase of this thesis was dedicated to determine the ability of aluminium to alter the oxidant status of specific brain areas, such as cerebellum, ventral midbrain, cortex, hippocampus, and striatum. Male Sprague-Dawley rats were intraperitoneally administered with aluminium chloride (10 mg Al3+/kg/day) in saline for 10 days. As we demonstrated before, this dosage procedure was sufficient to insure aluminium accumulation in brain areas. Animals were sacrificed 48 hours after lesion to perform lipid peroxidation and protein oxidation studies because the peak for oxidative 152
SUMMARY
stress is reached at this time as we previously reported in the first phase of this thesis. Our results showed that, except for hippocampus, the metal triggered an increase in oxidative stress levels (determined as TBARS, PCC, and PTC) for most of the brain regions studied, which was accompanied by decreased activities of the antioxidant enzymes (SOD, CAT, and GPx). However, studies in vitro confirmed the inability of aluminium to affect the activity of those enzymes and also of MAO-A and MAO-B. The reported effects exhibited a regional-selective behaviour for all the cerebral structures studied. Worthy of note is the case of the hippocampus, as aluminium exposure resulted in increased antioxidant enzymes activities, no significant alterations of lipid peroxidation and decreased protein oxidations. These results might be explained by the high aluminium accumulation and the promotion of compensatory mechanism(s) in this brain area. Lastly, and to shed some light on the potential of aluminium to act as an etiological factor in PD, we studied the ability of this metal to increase the striatal DAergic neurodegeneration and various indices of oxidative stress in ventral midbrain and striatum of rats injected intraventricularly with 6-OHDA. This animal model was known to induce a more slowly ensuing parkinsonian syndrome exhibiting similar topographic depletion of DAergic neurons to that observed in PD (Rodriguez et al. 2001, Rodríguez-Díaz et al. 2001) and to avoid the focal lesion around the cannula tip produced when 6-OHDA is directly injected in the brain tissues. We followed the same dosage procedure as previously mentioned (daily intraperitoneal injection of 10 mg mg Al3+/kg/day in saline for ten days) except that rats were lesioned on the 8th day with 6OHDA injected in the third ventricle. Animals were killed 1 week post-lesion for immunohistochemistry studies as it was reported that progressive degeneration of mesencephalic DAergic cells produced by intraventricular injection of 6-OHDA reached the definitive lesion pattern at the end of the first week postinjection (Rodriguez et al. 2001). Our results indicated that aluminium enhanced the ability of 6-OHDA to cause lipid peroxidation and protein oxidation (except for PTC in ventral midbrain). In addition, the metal was able to increase the capacity of 6-OHDA to cause
153
SUMMARY
neurodegeneration in the DAergic system as the loss of TH-ir striatal terminals was significantly increased.
Note: It is also important to note that all experiments carried out during this thesis were in accordance with the “Principles of laboratory animal care” (NIH publication No. 86-23, revised 1996) and approved by the corresponding Ethics Committee at the University of Santiago de Compostela. Furthermore, all efforts were made to reduce the number of animals used and to minimize animal suffering.
154
CONCLUSIONS
CONCLUSIONS
CONCLUSIONS
The results obtained in the present thesis led us to the following conclusions:
Chapter 1 1) Intrastriatal and unilateral injections of 6-OHDA cause a continuous and simultaneous increase in the indices of oxidative stress in the ipsilateral side, reaching a peak value at the 48 hours post-injection for both TBARS and PCC, and at 24 hours for PTC, and returning slowly to approximate control levels after 7-day post-injection in the case of TBARS, PCC and PTC. 2) The contralateral side should not be used as a control to assess neurochemical changes induced by 6-OHDA in this experimental model of PD as the unilateral injection of 6-OHDA causes a significant increase in the indices of oxidative stress, affecting both the striatum and the ventral midbrain, although lower than that found in the ipsilateral side. 3) The measurement of the brain indices of oxidative stress (TBARS and the content of oxidized groups in proteins) should be performed at 48-h following the intracerebral administration of 6-OHDA (peak-values time) when this model is used to assess new neuroprotective strategies or to study the oxidative potential of a specific etiological factor.
Chapter 2 4) Oral administration of aluminium chloride to rats for 4 weeks results in a significant increase in brain aluminium concentration in all the investigated brain areas (cerebellum, ventral midbrain, cortex, hippocampus and striatum).
157
CONCLUSIONS
5) Intraperitoneal aluminium chloride exposure to rats for one week causes a significant
and
greater
aluminium
accumulation
in
cerebellum,
cortex,
hippocampus and striatum, whereas a decrease in aluminium concentration is reported in ventral midbrain. 6) Aluminium administered i.p. predominantly accumulates in the hippocampus, whereas aluminium administered orally principally accumulates in the ventral midbrain. 7) Aluminium accumulation in the brain and its distribution in the different areas of the brain varie with the administration route used.
Chapter 3 8) Aluminium i.p. exposure to rats can create a situation of oxidative stress in most of the brain areas studied. 9) Aluminium causes a significant increase in the levels of TBARS in ventral midbrain, cortex and striatum, but particularly so in the cerebellum, while no significant changes is noted in the hippocampus. 10) Aluminium provokes a significant increase in both PCC and PTC in the cerebellum, ventral midbrain, and striatum, whereas a decrease is reported in the cortex and hippocampus. The molecular mechanism involved in the lack of a direct correlation between the increase observed in the PCC, and the “apparently” contradictory increase in PTC has not been found out. 11) All the brain regional areas examined show similar behaviour patterns as aluminium leads to a decrease of the enzyme activity of SOD, GPx, and CAT, except in hippocampus where antioxidant enzymes activities increase. 12) Aluminium does not significantly alter the enzyme activities of either of SOD, GPx, and CAT in vitro.
158
CONCLUSIONS
13) Aluminium does affect neither MAO-A nor MAO-B activity in vitro. 14) In this experimental model of PD aluminium causes an enhancement in 6-OHDAinduced lipid peroxidation and protein oxidation in vivo, except for PTC in ventral midbrain. 15) The administration of aluminium to control rats that were given intraventricularly saline instead of 6-OHDA also causes a significant difference in the levels of both lipid peroxidation and protein oxidation for PCC. 16) Immunohistochemical studies show that aluminium administration alone causes no significant change in TH-ir striatal terminals. In contrast, lesion with 6-OHDA causes a loss of TH-ir striatal terminals, which is significantly increased with the administration of aluminium.
According to the previously mentioned conclusions, we establish that the results here reported confirm the potential of aluminium as a risk factor in the development of PD. This metal acts mainly as a pro-oxidant and is able to reduce the activities of antioxidant enzymes. Its toxicity in the different brain areas studied (cerebellum, ventral midbrain, cortex, and striatum) is probably mediated by the contribution of AlO2●2+ and other free radical-induced oxidative cell damage. Interestingly, the results observed in the hippocampus (high aluminium content and not increased oxidant status) may be caused by specific compensatory mechanism(s) of the blood-hippocampal barrier but this idea still needs to be corroborated and characterized by future research.
159
RESUMEN
RESUMEN
RESUMEN Desde el punto de vista sanitario, el interés social que despierta el aluminio es cada vez mayor. Esto se debe a que la sociedad actual sufre una alta exposición a este metal y a que diversos estudios llevaron a considerar al aluminio como una sustancia capaz de causar neurodegeneración. Condiciones patológicas como la enfermedad de Parkinson han sido frecuentemente relacionadas con la acumulación de aluminio en el cerebro. Además, aunque el aluminio sea un metal inactivo desde el punto de vista redox, varios estudios han puesto de manifiesto que en determinadas circunstancias este metal potencia el estrés oxidativo cerebral. Sin embargo, el mecanismo molecular de su neurotoxicidad por el momento no es bien conocido. Por este motivo, decidimos profundizar en el conocimiento de los mecanismos de la neurotoxicidad del aluminio en procesos degenerativos inducidos por estrés oxidativo relacionados con la enfermedad de Parkinson. Para abordar esta investigación, resultaba imprescindible un conocimiento previo de la cinética del daño oxidativo inducido por la 6-OHDA en un modelo experimental de Parkinson, así como cuantificar los cambios observados en los índices de peroxidación lipídica y estado oxidativo de las proteínas en estriado y mesencéfalo ventral. Estos resultados nos permitirían conocer el momento exacto tras la administración intracerebral de 6-OHDA en el que efectuar la medida de estrés oxidativo cerebral para el estudio de los efectos oxidativos del aluminio. Para este estudio, elegimos la inyección unilateral e instraestriatal de 6-OHDA para lesionar la vía dopaminérgica nigroestriatal en ratas macho Sprague-Dawley. Este procedimiento ha sido frecuentemente utilizado para estudiar la degeneración de las neuronas dopaminérgicas características de la enfermedad de Parkinson. Si lo comparamos a otros modelos, con inyecciones de 6-OHDA en sustancia negra o tracto nigroestriatal, este método se aproxima más a la progresión de la enfermedad de Parkinson, puesto que conlleva una degeneración retrógrada del sistema nigroestriado más lenta, con un período de varias semanas (Sauer and Oertel 1994, Przedborski et al. 1995, Lee et al.
163
RESUMEN
1996, Shimohama et al. 2003). De hecho, esto nos permitió hacer un seguimiento de cinética con distintos grupos de ratas que abarcó un período de 7 días. Nuestros resultados indicaron claramente que la inyección unilateral e intraestriatal de 6-OHDA produce elevados niveles de peroxidación lipídica y de oxidación protéica en el mesencéfalo ventral y en el estriado. Para ambas regiones observamos un aumento durante los 2 primeros días después de la inyección y un retorno de los valores a niveles aproximados de control a los 7 días de la inyección. Los valores más altos fueron alcanzados a las 48 horas de la inyección para TBARS y para el contenido de grupos carbonilo en proteínas, y a las 24 horas para el contenido de grupos tiol en proteínas. Resultó interesante observar que en el lado contralateral (mesencéfalo ventral y estriado) se produce también un aumento significativo, aunque en menor cuantía, de los niveles de estrés oxidativo, hecho que desaconseja el uso de esa zona como control para determinar alteraciones neuroquímicas producidas por la 6-OHDA en este modelo experimental de Parkinson. Finalmente, y de acuerdo con los resultados obtenidos decidimos establecer el tiempo óptimo en 48 horas después de la inyección para cuantificar los niveles de estrés oxidativo cerebral en los ensayos sobre la capacidad oxidativa del aluminio en este modelo experimental de Parkinson. La segunda parte de esta tesis consistió en desarrollar un régimen de dosificación del aluminio en ratas, que garantizase una acumulación significativa de este metal en el cerebro, y con ello un conocimiento preciso de la distribución del aluminio en las regiones cerebrales. Puesto que previamente había sido demostrado que la distribución del aluminio depende de la especie animal en cuestión y de la fórmula química del aluminio administrado, optamos por utilizar dos vías distintas de administración: oral e intraperitoneal. Se usaron ratas Sprague-Dawley que fueron inyectadas diariamente por vía intraperitoneal con cloruro de aluminio (10 mg Al3+/kg/día) durante una semana, o bien recibieron por vía oral una dosis progresiva de cloruro de aluminio (25, 50, 100 mg Al3+/kg/día) y citrato (89, 178, 356 mg/kg/día) durante 4 semanas. Nuestros resultados indicaron que ambas vías de administración produjeron una acumulación de aluminio en cerebro. La acumulación fue mayor y más significativa para el grupo que recibía el aluminio por vía intraperitoneal en todas las
164
RESUMEN
zonas cerebrales excepto en el mesencéfalo ventral. La distribución también varió según el modo de administración. De acuerdo con estos resultados decidimos utilizar la vía de administración intraperitoneal para estudiar el estrés oxidativo cerebral producido por el aluminio. Finalmente dedicamos la tercera fase de esta tesis a determinar la capacidad del aluminio para alterar el estado oxidativo en áreas cerebrales específicas, tales como cerebelo, mesencéfalo ventral, corteza, hipocampo y estriado. Ratas macho SpragueDawley fueron inyectadas intraperitonealmente con cloruro de aluminio (10 mg Al3+/kg/día) en salino durante 10 días. Como demostramos previamente, esta dosificación era suficiente para asegurar una acumulación del aluminio en las regiones cerebrales estudiadas. Para realizar estudios de peroxidación lipídica y de oxidación protéica, los animales fueron sacrificados a las 48 horas después de la administración intraventricular de 6-OHDA porque, como comentamos anteriormente, el valor álgido de estrés oxidativo ocurre en ese momento. Nuestros resultados indicaron que, excepto para el hipocampo, el metal produjo un aumento en los niveles de estrés oxidativo (formación de TBARS y contenido de grupos carbonilo y tiol en proteínas) para la mayoría de las zonas cerebrales estudiadas, acompañado de un descenso en las actividades de las enzimas antioxidantes (superóxido dismutasa, catalasa y glutatión peroxidasa). Sin embargo, estudios in vitro confirmaron la incapacidad del aluminio para alterar la actividad de esos enzimas, así como también para afectar a la actividad de las monoamino oxidasas A y B. Los efectos observados presentan un comportamiento selectivo y regional para todas las estructuras estudiadas. Cabe destacar el caso del hipocampo, ya que la exposición al aluminio produjo un aumento de las actividades de las enzimas antioxidantes, una disminución de las oxidaciones protéicas y no alteró de manera significativa la peroxidación lipídica. Estos resultados pueden ser explicados por la alta acumulación de aluminio y el fomento de uno o varios mecanismos compensatorios en esa zona cerebral.
165
RESUMEN
Por último y con el fin de esclarecer el papel del aluminio como un posible factor etiológico de la enfermedad de Parkinson, hemos estudiado la capacidad de ese metal para aumentar la neurodegeneración dopaminérgica estriatal y los índices de estrés oxidativo en el mesencéfalo ventral y el estriado de ratas inyectadas intraventricularmente con 6-OHDA. Este modelo animal es conocido por inducir un síndrome
parkinsoniano
más
lento,
mostrando
una
depleción
de
neuronas
dopaminérgicas topográficamente similar (Rodriguez et al. 2001, Rodríguez-Díaz et al. 2001), y evitando la lesión focal alrededor de la punta de la cánula, producida cuando la 6-OHDA es introducida directamente en los tejidos cerebrales. Para la dosificación seguimos el procedimiento mencionado anteriormente (inyección i.p. diaria de 10 mg Al3+/kg/día durante 10 días), excepto que las ratas fueron lesionadas el octavo día con 6OHDA
inyectada
en
el
tercer
ventrículo.
Para
realizar
los
estudios
inmunohistoquímicos, los animales fueron sacrificados una semana después de la lesión, porque la degeneración progresiva de las células dopaminérgicas mesencefálicas producida por inyección intraventricular de 6-OHDA llega a un nivel definitivo de lesión una semana después de la inyección (Rodriguez et al. 2001). Nuestros resultados indicaron que el aluminio aumenta la capacidad de la 6-OHDA para causar peroxidación lipídica y oxidación protéica (excepto para el contenido de grupos tiol en proteínas en el mesencéfalo ventral). Además, el metal aumentó la capacidad de la 6OHDA para producir la neurodegeneración del sistema dopaminérgico, ya que la pérdida de terminales estriatales inmunoreactivas para la tirosina hidroxilasa aumentó de manera significativa.
Nota: Cabe destacar que todos los experimentos realizados a lo largo de esta tesis fueron conformes a la publicación del NIH, nº 86-23, revisada en 1996, “Principles of laboratory animal care”, y aprobados por el correspondiente Comité de Ética de la Universidad de Santiago de Compostela. Además, todos los esfuerzos fueron realizados para reducir la cantidad de animales utilizados y para minimizar el sufrimiento de los mismos.
166
CONCLUSIONES
CONCLUSIONES
CONCLUSIONES
Los resultados obtenidos a lo largo de esta tesis permitieron establecer las siguientes conclusiones:
Capítulo 1 1) Las inyecciones intraestriatales y unilaterales de 6-OHDA provocan un aumento continuo y simultáneo de los índices de estrés oxidativo en el lado ipsilateral, alcanzando un valor máximo 48 horas después de la inyección para TBARS y para el contenido de grupos carbonilo en proteínas, y a las 24 horas para el contenido de grupos tiol en proteínas. Los valores de TBARS, así como el contenido de grupos carbonilo y tiol en proteínas vuelven lentamente a los valores control después de 7 días tras la administración de 6-OHDA. 2) En este modelo experimental de Parkinson, el lado contralateral no debe ser utilizado como control para evaluar los cambios neuroquímicos inducidos por 6OHDA, dado que la inyección unilateral de 6-OHDA provoca un aumento significativo en los índices de estrés oxidativo, aunque en menor cuantía que los índices observados en el lado ipsilateral, afectando tanto el estriado como el mesencéfalo ventral. 3) Cuando este modelo experimental es utilizado para evaluar nuevas estrategias neuroprotectoras o para estudiar el potencial oxidativo de un posible factor etiológico, la cuantificación de niveles cerebrales de estrés oxidativo (TBARS y contenido de grupos oxidados en proteínas) debe llevarse a cabo 48 horas después de la administración intracerebral de 6-OHDA, que es el tiempo en el que se alcanzan los valores máximos.
169
CONCLUSIONES
Capítulo 2 4) La administración oral de cloruro de aluminio a ratas durante 4 semanas provoca un aumento significativo en la concentración cerebral de aluminio en todas las zonas estudiadas (cerebelo, mesencéfalo ventral, corteza, hipocampo y estriado). 5) La administración intraperitoneal de cloruro de aluminio a ratas durante una semana da lugar a una destacada e importante acumulación de aluminio en cerebelo, corteza, hipocampo y estriado, mientras que en mesencéfalo ventral se observa una disminución en la concentración de aluminio. 6) El aluminio administrado vía intraperitoneal se acumula de manera predominante en el hipocampo, mientras que el aluminio administrado oralmente se acumula principalmente en el mesencéfalo ventral. 7) Tanto la concentración de aluminio en cerebro como su distribución en las distintas áreas cerebrales varía dependiendo de la vía de administración usada para el aluminio.
Capítulo 3 8) La administración intraperitoneal de aluminio a ratas lleva a una situación de estrés oxidativo en la mayoría de las zonas cerebrales estudiadas. 9) El aluminio provoca un aumento destacado de los niveles de TBARS en mesencéfalo ventral, corteza y estriado, y sobre todo en cerebelo, mientras que no se hallan cambios significativos en hipocampo. 10) El aluminio ocasiona un aumento significativo en el contenido de grupos carbonilo y tiol en proteínas en cerebelo, mesencéfalo ventral y estriado, mientras que en corteza e hipocampo se observa una disminución. No se ha podido establecer el mecanismo molecular responsable de la falta de correlación directa entre el
170
CONCLUSIONES
aumento de grupos carbonilo observado en proteínas y el “aparentemente” contradictorio aumento en el contenido de grupos tiol. 11) Todas las regiones cerebrales examinadas muestran patrones similares, puesto que el aluminio induce una disminución de la actividad enzimática de la superóxido dismutasa, la glutatión peroxidasa y la catalasa, excepto en el hipocampo en el que la actividad de estos enzimas antioxidantes aumenta. 12) In vitro, el aluminio no modifica de manera significativa las actividades enzimáticas de la superóxido dismutasa, glutatión peroxidasa y catalasa. 13) In vitro, el aluminio no afecta a las actividades enzimáticas de la monoamino oxidasa A (MAO-A) ni de la monoamino oxidasa B (MAO-B). 14) In vivo, el aluminio provoca un aumento de la peroxidación lipídica y de la oxidación protéica inducidas por 6-OHDA en el modelo experimental de Parkinson utilizado, excepto para el contenido de grupos tiol en mesencéfalo ventral. 15) La administración de aluminio a ratas control a las que se administró intraventricularmente salino en lugar de 6-OHDA también provocó una variación significativa, tanto en el índice de peroxidación lipídica como en el estado oxidativo de proteínas en lo que respecta a contenido de grupos carbonilo. 16) Los estudios inmunohistoquímicos demuestran que la administración de aluminio solo no provoca cambio significativo de inmunoreactividad para tirosina hidroxilasa en las terminales estriatales. Sin embargo, la lesión con 6-OHDA causa una pérdida de inmunoreactividad de tirosina hidroxilasa en las terminales estriatales, que aumenta de manera significativa con la administración de aluminio.
171
CONCLUSIONES
En base a las conclusiones que se acaban de enumerar, establecemos, que los resultados expuestos confirman el potencial del aluminio como factor de riesgo en el desarrollo de la enfermedad de Parkinson. Este metal actúa principalmente como un pro-oxidante y es capaz de disminuir las actividades de los enzimas antioxidantes. Su toxicidad observada en las diferentes áreas cerebrales estudiadas (cerebelo, mesencéfalo ventral, corteza y estriado) probablemente se halla mediada por la contribución del anión superóxido de aluminio AlO2●2+ y por daños oxidativos a células inducidos por otros radicales libres. Cabe destacar que los resultados observados en el hipocampo (alto contenido en aluminio y estado oxidante no aumentado) pueden ser causados por uno o varios mecanismos compensatorios de la barrera hemato-hipocampal, pero esta idea necesita ser corroborada y caracterizada por investigaciones futuras.
172
APPENDIX
APPENDIX
Publications as a direct result from this thesis Sánchez-Iglesias S., Méndez-Álvarez E., Iglesias-González J., Muñoz-Patiño A., Sánchez-Sellero I., Labandeira-García J. L. and Soto-Otero R. (2009) Brain oxidative stress and selective behaviour of aluminium in specific areas of rat brain: potencial effects in a 6-OHDA-induced model of Parkinson‟s disease. J. Neurochem. 109, 879– 888. PMID: 19425176.
Sánchez-Iglesias S., Soto-Otero R., Iglesias-Gónzalez J., Barciela-Alonso M. C., Bermejo-Barrera P. and Méndez-Álvarez E. (2007) Analysis of brain regional distribution of aluminium in rats via oral and intraperitoneal administration. J. Trace Elem. Med. Biol. 21 Suppl. 1, 31–34. PMID: 18039493.
Sánchez-Iglesias S., Rey P., Méndez-Álvarez E., Labandeira-García J. L. and SotoOtero, R. (2007) Time course of brain oxidative damage caused by intrastriatal administration of 6-hydroxydopamine in a rat model of Parkinson‟s disease. Neurochem. Res. 32, 99–105. PMID: 17160721.
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APPENDIX
Publications arising from collaborative work during this thesis Soto-Otero R., Méndez-Álvarez E., Sánchez-Iglesia S., Zubko F. I., Voskressensky L. G., Varlamov A. V., De Candia M. and Altomare, C. (2008) Inhibition of 6hydroxydopamine-induced oxidative damage by 4,5-dihydro-3H-2-benzazepine Noxides. Biochem. Pharmacol. 75, 1526–37. PMID: 18275937.
Rey P., López-Real A., Sánchez-Iglesias S., Muñoz A., Soto-Otero R. and LabandeiraGarcía J. L. (2007) Angiotensin type-1-receptor antagonists reduce 6-hydroxydopamine toxicity for dopaminergic neurons. Neurobiol. Aging 28, 555–567. PMID: 16621167.
Soto-Otero R., Sanmartín-Suárez C., Sánchez-Iglesias S., Hermida-Ameijeiras A., Sánchez-Sellero I. and Méndez-Álvarez E. (2006) Study on the ability of 1,2,3,4tetrahydropapaveroline to cause oxidative stress: mechanisms and potential implications in relation to Parkinson‟s disease. J. Biochem. Mol. Toxicol. 20, 209–220. PMID: 17009235.
Hermida-Ameijeiras A., Méndez-Álvarez E., Sánchez-Iglesias S., Sanmartín-Suárez C. and Soto-Otero R. (2004) Autoxidation and MAO-mediated metabolism of dopamine as a potential cause of oxidative stress: role of ferrous and ferric ions. Neurochem. Int. 45, 103–116. PMID: 15082228.
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