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适用于中风。纤维类药物最初是作为降血脂化合物开发的，是过氧化物酶体增殖物激活受体（PPAR） a激动剂，对心血管系统具有多种生物作用。过氧化物酶体是一种单膜细胞器，参与长链脂肪酸的氧化、胆汁酸合成、胆固醇合成、质脲原合成、氨基酸代谢和嘌呤代谢。贝特类药物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，一种震颤类化合物，吉非罗齐，可降低冠心病患者中风的发生率。证据表明PPARa激动剂是预防或治疗中风的潜在药物。我们最近证明了两种PPARa激动剂，非诺贝特和Wy-14643，在野生型小鼠永久性局灶性脑缺血后有明显的梗死面积减少。这一提议旨在验证我们的一般假设，即PPAR激活保护大脑免受缺血性中风。实验旨在通过将分子和生化技术与具有良好特征的小鼠脑卒中模型永久性大脑中动脉闭塞相结合来扩展我们的初步发现。我们提出了两个具体的目的来证明贝特类药物通过双重机制改善卒中预后：(1)早期血流动力学机制；(2)迟发性血管损伤（炎症）机制。我们将在野生型和PPARa敲除小鼠中使用非诺贝特和Wy-14643作为PPARa激动剂。我们的初步研究表明，非诺贝特可以改善大脑中动脉闭塞后野生型小鼠缺血脑的脑血流量。提出的研究将更好地了解这些药物对中风的保护模式。

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 for stroke. Fibrates, originally developed as hypolipidemic compounds, are peroxisome proliferator-activated receptor (PPAR) a agonists, and exhibit several biological actions on the cardiovascular system. Peroxisome is a single-membrane organelle and participates in ¿-oxidation of long fatty acids, bile acid synthesis, cholesterol synthesis, plasmalogen synthesis, amino acid metabolism, and purine metabolism. Fibrates have been shown to protect the heart and kidney against ischemia/reperfusion. A clinical trial demonstrated that a tibrate class compound, gemfibrozil, reduces stroke incidence in men with coronary heart disease. The evidence suggests that PPARa agonists are potential drugs to prevent or treat stroke. We recently demonstrated that two PPARa agonists, fenofibrate and Wy-14643, have a robust reduction in infarct size after permanent focal cerebral ischemia in wild-type mice. This proposal aims to test our general hypothesis that PPAR activation protects the brain against ischemic stroke. Experiments are designed to extend our preliminary findings by combining molecular and biochemical techniques with the well-characterized mouse stroke model, permanent middle cerebral artery occlusion. Two specific aims are proposed to demonstrate that fibrates improve stroke outcome through the dual mechanisms: (1) early hemodynamic mechanism; and (2) delayed vascular injury (inflammation) mechanism. We will use fenofibrate and Wy-14643 as PPARa agonists in wild-type and PPARa knockout mice. Our preliminary studies demonstrated that fenofibrate improves cerebral blood flow in ischemic brain in wild-type mice after middle cerebral artery occlusion. The proposed studies will provide a better understanding about the mode of stroke protection by these drugs.