New Target For Stroke: Peroxisome Proliferator Activated Receptor-Gamma

描述(申请人提供)：利用原代脑细胞培养和全动物系统建立过氧化体增殖物激活受体-y(PPARy)促生存功能的潜在机制PPARy的脑血管作用尚未得到充分研究。在我们的初步研究中，我们证明了激活PPARy(噻唑烷二酮(TZDS)和环戊酮前列腺素(CyPG)的治疗可以减少缺血性中风和脑出血模型大鼠的细胞死亡、炎症、梗死体积和行为功能障碍。在胰岛素抵抗患者中使用吡格列酮(一种PPARy激动剂)进行的一项临床多中心随机试验，旨在确定最近发生的缺血性中风患者的致命性或非致命性中风的风险，临床前背景有限。大约有700万美国人每天因胰岛素抵抗而服用TZDS。由于患有胰岛素抵抗的人患中风的风险很高，这些药物可能不仅对急性中风的治疗有用，还可能用于增强大脑对未来脑血管事件的抵抗力。本提案旨在研究PPARy在缺氧缺糖细胞培养中的细胞学基础，利用转基因小鼠确定PPARy在缺血中的作用，并在已建立的在体大鼠中风模型中测试PPARy配体的药理作用。我们建议测试以下具体目标。1.利用原代培养的脑细胞，建立PPARy促生存功能的机制。2.利用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包含一个功能性的PPAR反应元件)和4)转录因子核因子-kappa-B(核因子-kappaB；核因子-kappa-B被PPARy抑制)的局灶性脑缺血模型和基因工程小鼠，建立PPARy抗缺血作用的机制。3.评价PPARy激动剂抗缺血活性的最佳条件(药物选择、剂量、有效治疗的时间窗、耐受性和对永久性与可逆性缺血的有效性)。

DESCRIPTION (provided by applicant): 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. In 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 launched 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 following specific aims. 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 underlying the 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.