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. ? ?
