Peroxisome Proliferator-Activated Receptor and Stroke

描述（由申请人提供）：缺血性中风是脑动脉血流不足导致的一组复杂的细胞紊乱。因此，具有多效性的药物可能更可行。纤维类药物最初是作为降血脂化合物开发的，是增殖激活受体（PPAR）受体激动剂，对心血管系统具有多种生物作用。它们已被证明可以保护心脏和肾脏免受缺血/再灌注。一项临床试验表明，一种贝特类化合物，吉非罗齐，可降低冠心病患者中风的发生率。有证据表明，PPAR激动剂是预防或治疗中风的潜在药物。然而，没有研究检验贝特类药物是否能够减少中风后脑梗死面积。此外，PPAR在缺血性脑卒中中的作用尚未明确。本研究旨在验证我们的一般假设，即PPAR激活在缺血/再灌注后保护大脑。结合分子生化技术，结合表征良好的小鼠脑卒中模型设计实验，2小时大脑中动脉闭塞，其中再灌注损伤起显著作用。

DESCRIPTION (provided by applicant): Ischemic stroke is a complex set of cellular disturbances as a consequence of cerebral arterial flow insufficiency. Therefore, drugs exhibiting pleiotropic effects may be more feasible. Fibrates, originally developed as hypolipidemic compounds, are proliferator-activated receptor (PPAR) o_ agonists, and exhibit several biological actions on the cardiovascular system. They have been shown to protect the heart and kidney against ischemia/reperfusion. A clinical trial demonstrated that a fibrate class compound, gemfibrozil, reduces stroke incidence in men with coronary heart disease. The evidence suggests that PPAR agonists are potential drugs to prevent or treat stroke. However, no studies have examined whether fibrates are able to reduce brain infarct size after stroke. In addition, the role of PPAR in ischemic stroke has not been clarified. This proposal aims to test our general hypothesis that PPAR activation protects the brain after ischemia/reperfusion. Combining molecular and biochemical techniques with the well characterized mouse stroke model design experiments, 2 hours of middle cerebral artery occlusion, where reperfusion injury plays a significant role. Four Specific Aims are proposed to test our hypotheses that: (1) PPAR agonists protect the brain against ischemia/reperfusion; (2) PPAR activation protects the brain against ischemia/reperfusion; (3) PPAR agonists activate PPAR after ischemia/reperfusion; (4) PPAR agonists attenuate inflammatory reactions including nuclear factor kappa B activation, cytokine production, and protease release after ischemia/reperfusion. We will use fenofibrate, Wy-14643, and resveratrol as PPAR agonists. Our preliminary studies demonstrated that resveratrol activates both PPAR and PPARy in several types of cells. The proposed studies will clarify the potency of the PPAR agonists for stroke therapy, and will provide essential information about the mode of protection by these drugs.