Peroxisome Proliferator-Activated Receptor and Stroke

过氧化物酶体增殖物激活受体和中风

• 批准号: 7244926
• 负责人: SHOBU NAMURA
• 金额: $ 0.74万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244926
• 关键词: Peroxisome; Proliferator; Activated; Receptor; Stroke

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.

描述(由申请人提供)：缺血性中风是一组复杂的细胞紊乱，是脑动脉血流不足的结果。因此，具有多效性的药物可能更可行。贝特最初是一种降血脂化合物，是一种增殖物激活受体(PPAR)受体激动剂，对心血管系统具有多种生物学作用。它们已被证明可以保护心脏和肾脏免受缺血/再灌流的影响。一项临床试验表明，贝特类化合物吉非罗齐可以降低男性冠心病患者的中风发生率。证据表明，PPAR激动剂是预防或治疗中风的潜在药物。然而，还没有研究检验贝特类药物是否能够减少中风后的脑梗塞面积。此外，PPAR在缺血性卒中中的作用尚未阐明。这项建议旨在验证我们的普遍假设，即PPAR激活在缺血/再灌流后保护大脑。结合分子和生化技术与有良好特点的小鼠卒中模型设计实验，大脑中动脉闭塞2小时，在脑缺血再灌注损伤中起重要作用。 为了验证我们的假设，我们提出了四个特定的目标：(1)PPAR激动剂保护脑缺血/再灌注；(2)PPAR激动剂保护脑缺血/再灌流；(3)PPAR激动剂在缺血/再灌流后激活PPAR；(4)PPAR激动剂减轻炎症反应，包括缺血/再灌流后核因子-kappaB的激活、细胞因子的产生和蛋白酶的释放。我们将使用非诺贝特、Wy-14643和白藜芦醇作为PPAR激动剂。我们的初步研究表明，白藜芦醇在几种类型的细胞中同时激活PPAR和PPARy。拟议的研究将阐明PPAR激动剂在中风治疗中的效力，并将提供关于这些药物保护模式的基本信息。