New Target For Stroke: Peroxisome Proliferator Activated Receptor-Gamma

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To establish, using primary brain cell cultures and whole animal system the mechanisms underlying pro- survival function of Peroxisome Proliferator Activated Receptor-y(PPARy) The cerebrovascular role of PPARy is understudied, hi our preliminary studies we demonstrated that treatments that activate PPARy (thiazolidinediones (TZDs) and cyclopentanone prostaglandins (CyPG) reduce cell death, inflammation, infarct volume and behavioral dysfunction in rat models of ischemic stroke and intracerebral hemorrhage. A clinical multi-center randomized trial with pioglitazone (a PPARy agonist), in insulin resistant patients, aiming at determining risk for fatal or non-fatal stroke in patients with recent ischemic stroke, has been lanched with limited pre-clinical background. Approximately 7 million Americans take TZDs daily for insulin resistance. Since people with insulin resistance are at high risk for stroke, these drugs may prove useful not only for management of the acute stroke, but may also be used to augment the brain's resistance to future cerebrovascular events. The present proposal seeks to investigate the cellular basis of PPARy in cell culture subjected to oxygen glucose deprivation, determine the role of PPARy in ischemia using genetically altered mice, and test the pharmacologic effects of PPARy ligands in a well-established in vivo rat stroke model. We propose to test the followingspecificaims. 1. To establish, using primary brain cell cultures, the mechanisms underlying pro-survival function of PPARy. 2. Utilizing a well-characterized focal ischemia model and genetically engineered mice with disrupted 1) neuronal-and 2) microglia/macrophage- PPARy, 3) catalase (catalase gene promoter contains a functional PPAR responsive element), and 4) the transcription factor, nuclear factor kappa-B (NF-KB; NF-KB is inhibited by PPARy),to establish mechanisms underlyingthe anti-ischemic role of PPARy. 3. To evaluate optimal conditions (selection of drug, dose, time window for effective treatment, tolerance, and effectiveness in permanent vs. reversible ischemia) for the anti-ischemic activity of PPARy agonists.