New Target For Stroke: Peroxisome Proliferator Activated Receptor-Gamma

利用原代脑细胞培养和整个动物系统，建立促凋亡的潜在机制， 过氧化物酶体激活受体γ（PPARy）生存功能 PPARy的脑血管作用尚未充分研究。在我们的初步研究中，我们证明， 激活PPARy（噻唑烷二酮（TZD）和环戊酮异戊烯二酮（CyPG））的治疗 减少缺血性中风大鼠模型中的细胞死亡、炎症、梗死体积和行为功能障碍 和脑内出血吡格列酮（一种PPARy激动剂）临床多中心随机试验， 在胰岛素抵抗患者中，旨在确定近期有 缺血性中风，已被推出有限的临床前背景。大约700万美国人 每天服用TZD治疗胰岛素抵抗由于胰岛素抵抗的人中风的风险很高， 药物不仅可用于急性卒中的治疗，而且可用于增强 大脑对未来脑血管事件的抵抗力。 本发明旨在研究PPARy在经受氧的细胞培养物中的细胞基础。 葡萄糖剥夺，使用基因改变的小鼠确定PPARy在缺血中的作用，并测试PPARy在缺血中的作用。 图10显示了PPARy配体在良好建立的体内大鼠中风模型中的药理学作用。 我们建议测试以下具体目标。 1.使用原代脑细胞培养物，建立促存活功能的潜在机制， PPARy。 2.利用充分表征的局灶性缺血模型和具有破坏的1） 神经元-和2）小胶质细胞/巨噬细胞- PPARy，3）过氧化氢酶（过氧化氢酶基因启动子含有功能性的 4）转录因子，核因子κ-B（NF-κ B; NF-κ B是核转录因子。 抑制），以建立PPARy抗缺血作用的机制。 3.评价最佳条件（药物选择、剂量、有效治疗时间窗、耐受性， 和在永久性与可逆性局部缺血中的有效性）。

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.