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: 7122507
• 负责人: SHOBU NAMURA
• 金额: $ 27.73万
• 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/7122507
• 关键词: brain circulation; brain injury; chemoprevention; clofibrate; disease /disorder model; drug screening /evaluation; gel mobility shift assay; immunocytochemistry; inflammation; laboratory mouse; laser Doppler flowmetry; neuroprotectants; nonhuman therapy evaluation; nuclear factor kappa beta; peroxisome proliferator activated receptor; polymerase chain reaction; pyrimidines; radiotracer; receptor expression; stroke therapy; western blottings

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.

描述（由申请人提供）：缺血性卒中是一组复杂的细胞紊乱，是脑动脉血流不足的结果。因此，显示多效性作用的药物可能更适用于中风。贝特类化合物是一种过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR-a）激动剂，对心血管系统具有多种生物学作用。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、缩醛原合成、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，替贝特类化合物吉非贝齐可降低冠心病男性的中风发病率。有证据表明，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具有显著的梗死面积减小。该提议旨在验证我们的一般假设，即PPAR激活可保护大脑免受缺血性卒中的影响。实验的目的是扩大我们的初步研究结果相结合的分子和生物化学技术的特点，小鼠中风模型，永久性大脑中动脉闭塞。提出了两个具体目的，以证明贝特类药物通过双重机制改善卒中结局：（1）早期血流动力学机制;（2）延迟性血管损伤（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，非诺贝特改善野生型小鼠大脑中动脉闭塞后缺血脑的脑血流量。拟议的研究将更好地了解这些药物的中风保护模式。