Arachidonic acid metabolites, prostaglandins and leukotrienes, have been implicated as important mediators of the inflammatory response after tissue injury. Although there is good evidence that certain classes of prostaglandins and leukotrienes are produced within the central nervous system (CNS), the contribution these factors make to neuropathic conditions remains uncertain. In order to uncover mechanisms that regulate cellular events during the early phase of CNS damage, our laboratory has developed methods to isolate and grow specific populations of CNS glia, to identify brain cells by a variety of immunohistochemical techniques, and to monitor in vivo a number of tissue responses to CNS injury. Our investigations of the damaged CNS mesh nicely with the biochemical expertise of Wu and collaborators. We Propose a joint study to examine some simple but fundamentally important issues regarding brain eicosanoids. Using highly enriched cultures of microglia, astroglia, and oligodendroglia as well as preparations of neurons, we will characterize arachidonic acid metabolism for specific classes of cells within the nervous system. We will test the ability of immunomodulators to stimulate the production of brain eicosanoids including prostaglandins and leukotrienes. We will also determine the effectiveness of a variety of drugs to inhibit brain eicosanoid metabolism in vitro. In vivo studies will complement the examination of brain cell cultures. We will measure arachidonic acid metabolites in regions of penetrating brain injury and at sites of spinal cord infarction. Based upon these studies, we will next determine the ability of prostaglandins and leukotrienes to open the blood brain barrier, and to induce tissue edema in rat cerebral cortex or rabbit spinal cord. We will also investigate the in vivo action of immunomodulators as well as a variety of inhibitory drugs upon brain arachidonic acid metabolism. If successful, this proposed research will establish the cellular sources of brain prostaglandins and leukotrienes, will determine the contribution of eicosanoids to brain inflammation, and will assess the benefits of drug therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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Chen, Pei-Feng; Wu, Kenneth K (2009) Two synthetic peptides corresponding to the proximal heme-binding domain and CD1 domain of human endothelial nitric-oxide synthase inhibit the oxygenase activity by interacting with CaM. Arch Biochem Biophys 486:132-40
Wu, Jui-Sheng; Cheung, Wai-Mui; Tsai, Yau-Sheng et al. (2009) Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation. Circulation 119:1124-34
Liou, Jun-Yang; Ellent, David P; Lee, Sang et al. (2007) Cyclooxygenase-2-derived prostaglandin e2 protects mouse embryonic stem cells from apoptosis. Stem Cells 25:1096-103
Liou, Jun-Yang; Lee, Sang; Ghelani, Dipak et al. (2006) Protection of endothelial survival by peroxisome proliferator-activated receptor-delta mediated 14-3-3 upregulation. Arterioscler Thromb Vasc Biol 26:1481-7
Cieslik, Katarzyna A; Deng, Wu-Guo; Wu, Kenneth K (2006) Essential role of C-Rel in nitric-oxide synthase-2 transcriptional activation: time-dependent control by salicylate. Mol Pharmacol 70:2004-14
Deng, Wu-Guo; Tang, Shao-Tzu; Tseng, Hui-Ping et al. (2006) Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 108:518-24
Wu, Kenneth K (2006) Analysis of protein-DNA binding by streptavidin-agarose pulldown. Methods Mol Biol 338:281-90
Lin, Teng-Nan; Cheung, Wai-Mui; Wu, Jui-Sheng et al. (2006) 15d-prostaglandin J2 protects brain from ischemia-reperfusion injury. Arterioscler Thromb Vasc Biol 26:481-7
Wu, Kenneth K (2006) Transcription-based COX-2 inhibition: a therapeutic strategy. Thromb Haemost 96:417-22
Liou, Jun-Yang; Aleksic, Nena; Chen, Shu-Fen et al. (2005) Mitochondrial localization of cyclooxygenase-2 and calcium-independent phospholipase A2 in human cancer cells: implication in apoptosis resistance. Exp Cell Res 306:75-84

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