PRIORITY PAPER EVALUATION

Cyclooxygenase-2 regulation of brain lipid composition Eduardo Candelario-Jalil University of New Mexico, Department of Neurology, Health Sciences Center MSC10 5620, 915 Camino de Salud NE, Albuquerque, NM 87131-0001, USA Tel.: +1 505 925 4042; Fax: +1 505 272 6692; [email protected]

Keywords: brain injury, cyclooxygenase, fatty acids, gene expression, lipid composition, neuroinflammation part of

Evaluation of: Ma K, Langenbach R, Rapoport SI, Basselin M: Altered brain lipid composition in cyclooxygenase-2 knockout mouse. J. Lipid Res. 48, 848–854 (2007). This study investigated for the first time the effects of life-long absence of cyclooxygenase (COX)-2 on brain lipid composition using COX-2 null mice. Concentrations of different lipids were measured in the brains of COX-2 knockout and wild-type mice. The authors found multiple changes in brain lipid content as demonstrated by a significant increase in phosphatidylserine (PtdSer) and unesterified arachidic acid, and reduction in triacylglycerol and cholesterol concentrations. These data suggest that lack of COX-2 dramatically alters the brain lipid composition in the COX-2 knockout mouse. Thus, results from this report could have important implications for the interpretation of data from previous and future studies using COX-2 null mice.

Ma and colleagues report for the first time the effect of COX-2 gene deletion on lipid composition in the mouse brain [1]. Prostaglandins and thromboxanes are formed in vivo from arachidonic acid (AA). The first step in the AA metabolic cascade is catalyzed by prostaglandin endoperoxide H synthase, also known as cyclooxygenase (COX). Two isoforms of the COX gene (COX-1 and COX-2) have been described [2], and a new splice variant of COX-1, termed COX-3, has been identified in the brain [3–6]. COX has two different catalytic activities: cyclooxygenase and peroxidase. The first converts AA into PGG2, an endoperoxide that is quickly transformed into PGH2 by the peroxidase activity of COX. Then, terminal tissue-specific synthases form prostaglandins and thromboxanes using PGH2 as a common substrate. It is widely accepted that COX-1 is a constitutive enzyme responsible for the formation of physiological levels of prostanoids [2]. COX-2 is highly inducible by mitogens, growth factors, hormones and proinflammatory stimuli. Thus, COX-2 has been referred as the ‘inducible’ isoform [2,7]. However, COX-2 is present under normal conditions in certain neuronal populations, and it is linked to synaptic activity [7]. COX-2 expression is also present in the kidney, where it is involved in the maintenance of renal blood flow [2]. Gene deletion technology is based on the inactivation of a gene of interest to provide a mechanism to study its function. The studies of COX-1 and COX-2 null mice have provided a valuable insight into the physiological functions, as well as the pathological role, of each COX

10.2217/17460875.2.4.399 © 2007 Future Medicine Ltd ISSN 1746-0875

isoform. COX-1 knockout mice were born after an expected gestational term and show a normal lifespan, even though their levels of prostanoids were dramatically reduced in most tissues [8]. An impairment of platelet aggregation was observed in the COX-1 null mice [8]. In addition, although COX-1 knockout female mice produced litters of normal size, they had difficulty with parturition, and most pups were stillborn or died shortly after birth. No gastric or kidney pathologies were observed in COX-1 knockouts [8]. This is surprising given the ‘housekeeping’ functions attributed to COX-1. COX-1 knockout mice showed a significant decrease in resting cerebral blood flow and impaired vasodilatory responses [9]. Mice lacking COX-2 expression manifested several pathologies [10,11]. COX-2-deficient female mice were essentially infertile, while male knockout mice showed normal fertility. Profound renal abnormalities were observed in all adult COX-2 null mice [11]. It is important to highlight significant compensatory changes in gene expression observed in COX-deficient mice. COX-1 null mice have upregulated brain expression and activity of Ca2+-dependent phospholipase A2 (cPLA2) and secretory PLA2 (sPLA2), as well as an increase in the expression of COX-2 [12]. These animals also manifest increased brain levels of prostaglandin E2 (PGE2) and increased activation of the transcription factor NF-κB [12]. COX-2-deficient mouse brains show a significant upregulation of the enzymatic activity as well as the expression of both cPLA2 and sPLA2, and a compensatory increase in the expression of COX-1 [13]. Brain PGE2 concentrations are Future Lipidol. (2007) 2(4), 399–402

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PRIORITY PAPER EVALUATION – Candelario-Jalil

decreased by approximately 50% in the COX-2 knockout mice compared with wild type despite a compensatory increase in COX-1 expression [13]. Furthermore, COX-2-deficient mice show a significant decrease in NF-κB activity, which could be caused by the decrease in the protein levels of p65, phosphorylated I-κBα and phosphorylated p65 [14]. As previously suggested [15], these changes in the NF-κB transcription factor suggest that COX-2 inactivation may in turn have significant transcriptional consequences. In a very recent study [16], gene expression in the brain of mice deficient in either COX-1 or COX-2 was investigated. This elegant study using microarray analysis and quantitative PCR found that the expression of genes involved in β oxidation of lipids and methionine metabolism is upregulated in the cortex of COX-2 null mice. In addition, significant changes were observed in the expression of GABA transporter, GABA-A receptor subunit β1, and Janus kinase (JAK) isoforms 1 and 2 in COX-1 and COX-2 knockout mice [16]. These data indicate that COXderived prostanoids can significantly modulate gene expression in the brain. Results from the paper

This investigation addressed the role of COX-2 in brain lipid composition by utilizing COX-2 null mice and their wild-type counterparts [1]. Authors used head-focused high-energy microwave irradiation to stop brain metabolism, and thus were able to accurately measure lipid composition. Total lipids from frozen brain were extracted following standard procedures. This experimental approach had been previously utilized and standardized by the authors [17,18]. COX-2 knockouts displayed a significant increase in phosphatidylserine (PtdSer) and a decrease in triacylglycerol, cholesterol and cholesterol-to-phospholipid ratio. In addition, brain concentration of unesterified arachidic acid was significantly increased in COX-2 null mice as compared with wild-type controls. The concentration of esterified palmitic acid in cholesteryl ester was significantly less in COX-2 null mice than in wild type. COX-2 deficient mice also showed a dramatic increase (62%) of esterified palmitate in PtdSer.

changes in the expression and activity of PLA2 enzymes [13]. This finding is in agreement with a recent report showing higher rates of AA loss in COX-2 knockouts compared with wild-type mice [19]. Taken together with previous reports [13,16,19], results from the study of Ma and colleagues are very interesting and convincingly illustrate that the lack of COX-2 dramatically alters the brain lipid composition in this knockout mouse [1]. COX-2 has been implicated in neuroinflammation following different types of brain injury [7,20]. COX-2 null mice have been utilized to determine the neuropathological role of COX-2. Previous reports indicate that mice lacking the COX-2 gene showed a reduced susceptibility to cerebral ischemia [21,22], excitotoxicity induced by cortical microinjection of N-methylD-aspartate (NMDA) [21], and neurotoxicity mediated by (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine [MPTP]) [23] and kainic acid [24]. As pointed out by Ma and colleagues [1], some of the abnormalities in brain lipid composition, as shown in their study for the first time, may contribute to the resistance to neurotoxic insults in COX-2 knockout mice. This suggests that the reduced vulnerability to brain injury might not only be due to the absence of ‘bad’ COX-2 activity, but also due to profound alterations in the composition of brain lipids in these knockout mice. The mechanisms through which an increase in brain PtdSer and a significant decrease in total cholesterol in COX-2 null mice might impact their susceptibility to cerebral damage are carefully discussed in the article [1]. These findings, together with the results of Toscano and colleagues, could have important implications for the interpretation of data from previous studies using COX-2 null mice [16]. The resistance to brain injury observed in COX-2-deficient mice is due not only to reduced prostanoid and free radical production, but also to significant changes in brain lipid composition [1] and profound changes in gene expression patterns [13,14,16]. However, the deleterious role of COX-2 in neuroinflammation following brain injury has been also demonstrated pharmacologically by using highly selective COX-2 inhibitors [20,22–25]. Future perspective

Significance of the results

The paper by Ma and coworkers extends our knowledge of the functional consequence of COX-2 ablation on brain lipid metabolism [1]. Lifelong absence of the COX-2 gene results in 400

Future Lipidol. (2007) 2(4)

The findings of Ma and coworkers add significant information of the effects of lifelong absence of COX-2 on the lipid composition of the brain [1]. However, it remains to be determined whether COX-2 knockout mice also future science group

Cyclooxygenase-2 regulation of brain lipid composition – PRIORITY

exhibit altered lipid composition in other tissues, and how this would affect physiological function(s) as well as response to peripheral inflammation. In addition, it would be of great interest to investigate whether chronic administration

PAPER EVALUATION

of COX inhibitors produces significant changes in tissue lipid composition. This would potentially broaden our understanding of the pharmacologic and toxicologic consequences of COX inhibition.

Executive summary • Findings from this study indicate that lifetime ablation of COX-2 results in significant changes in brain lipid content. • COX-2 knockout mice showed an altered brain lipid composition (increase in phosphatidylserine [PtdSer], unesterified arachidic acid and esterified palmitate in PtdSer, together with a significant reduction in triacylglycerol and cholesterol). • Abnormalities in brain lipid composition may contribute to the resistance to neurotoxic insults observed in COX-2 null mice. • Interpretation of data from previous studies using COX-2 knockout mice should be undertaken with care. • It remains to be determined whether lipid composition is also altered following chronic administration of COX inhibitors. Bibliography Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. Ma K, Langenbach R, Rapoport SI, Basselin M: Altered brain lipid composition in cyclooxygenase-2 knockout mouse. J. Lipid Res. 48, 848–854 (2007). 2. Smith WL, DeWitt DL, Garavito RM: Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69, 145–182 (2000). 3. Chandrasekharan NV, Dai H, Roos KL et al.: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure and expression. Proc. Natl Acad. Sci. USA 99, 13926–13931 (2002). 4. Shaftel SS, Olschowka JA, Hurley SD, Moore AH, O’Banion MK: COX-3: a splice variant of cyclooxygenase-1 in mouse neural tissue and cells 362. Brain Res. Mol. Brain Res. 119, 213–215 (2003). 5. Kis B, Snipes JA, Gaspar T et al.: Cloning of cyclooxygenase-1b (putative COX-3) in mouse. Inflamm. Res. 55, 274–278 (2006). 6. Snipes JA, Kis B, Shelness GS, Hewett JA, Busija DW: Cloning and characterization of cyclooxygenase-1b (putative cyclooxygenase-3) in rat. J. Pharmacol. Exp. Ther. 313, 668–676 (2005). 7. Hewett SJ, Bell SC, Hewett JA: Contributions of cyclooxygenase-2 to neuroplasticity and neuropathology of the

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central nervous system. Pharmacol. Ther. 112, 335–357 (2006). Excellent review article discussing the most recent evidence implicating COX-2 in neurophysiology and neuropathology Langenbach R, Morham SG, Tiano HF et al.: Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acidinduced inflammation and indomethacininduced gastric ulceration. Cell 83, 483–492 (1995). Niwa K, Haensel C, Ross ME, Iadecola C: Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation. Circ. Res. 88, 600–608 (2001). Morham SG, Langenbach R, Loftin CD et al.: Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 83, 473–482 (1995). Dinchuk JE, Car BD, Focht RJ et al.: Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 378, 406–409 (1995). Choi SH, Langenbach R, Bosetti F: Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-κB pathway and downstream enzymes involved in prostaglandin biosynthesis. J. Neurochem. 98, 801–811 (2006). Bosetti F, Langenbach R, Weerasinghe GR: Prostaglandin E2 and microsomal prostaglandin E synthase-2 expression are decreased in the cyclooxygenase-2-deficient mouse brain despite compensatory induction of cyclooxygenase-1 and Ca2+dependent phospholipase A2. J. Neurochem. 91, 1389–1397 (2004).

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First study demonstrating the occurrence of important compensatory changes in arachidonic acid-metabolizing enzymes in COX-2 knockout mice Rao JS, Langenbach R, Bosetti F: Downregulation of brain nuclear factor-κB pathway in the cyclooxygenase-2 knockout mouse. Brain Res. Mol. Brain Res. 139, 217–224 (2005). Bosetti F: Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models. J. Neurochem. (In press) (2007). Toscano CD, Prabhu VV, Langenbach R, Becker KG, Bosetti F: Differential gene expression patterns in cyclooxygenase-1 and cyclooxygenase-2 deficient mouse brain. Genome Biol. 8(1), R14 (2007). This outstanding study showed for the first time that COX-1 and COX-2 differentially modulate brain gene expression. Rosenberger TA, Villacreses NE, Contreras MA, Bonventre JV, Rapoport SI: Brain lipid metabolism in the cPLA2 knockout mouse. J. Lipid Res. 44, 109–117 (2003). Bazinet RP, Lee HJ, Felder CC et al.: Rapid high-energy microwave fixation is required to determine the anandamide (Narachidonoylethanolamine) concentration of rat brain. Neurochem. Res. 30, 597–601 (2005). Basselin M, Villacreses NE, Langenbach R et al.: Resting and arecoline-stimulated brain metabolism and signaling involving arachidonic acid are altered in the cyclooxygenase-2 knockout mouse. J. Neurochem. 96, 669–679 (2006).

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Candelario-Jalil E, Gonzalez-Falcon A, Garcia-Cabrera M, Leon OS, Fiebich BL: Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood–brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats. J. Neurochem. 100, 1108–1120 (2007). Iadecola C, Niwa K, Nogawa S et al.: Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc. Natl Acad. Sci. USA 98, 1294–1299 (2001).

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Sasaki T, Kitagawa K, Yamagata K et al.: Amelioration of hippocampal neuronal damage after transient forebrain ischemia in cyclooxygenase-2-deficient mice. J. Cereb. Blood Flow Metab. 24, 107–113 (2004). Vijitruth R, Liu M, Choi DY et al.: Cyclooxygenase-2 mediates microglial activation and secondary dopaminergic cell death in the mouse MPTP model of Parkinson's disease. J. Neuroinflammation 3, 6 (2006). Takemiya T, Maehara M, Matsumura K et al.: Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region. Neurosci. Res. 56, 103–110 (2006).

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Sugimoto K, Iadecola C: Delayed effect of administration of COX-2 inhibitor in mice with acute cerebral ischemia. Brain Res. 960, 273–276 (2003).

Affiliation • Eduardo Candelario-Jalil, PhD University of New Mexico, Department of Neurology, Health Sciences Center MSC10 5620, 915 Camino de Salud NE, Albuquerque, NM 87131-0001, USA Tel.: +1 505 925 4042; Fax: +1 505 272 6692; [email protected]

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Cyclooxygenase-2 regulation of brain lipid composition

Furthermore, COX-2-deficient mice show a sig- ... be caused by the decrease in the protein levels of ... receptor subunit β1, and Janus kinase (JAK) isoforms 1 ...

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