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. ? ? ?
|Wang, Guangming; Namura, Shobu (2011) Effects of chronic systemic treatment with peroxisome proliferator-activated receptor ýý activators on neuroinflammation induced by intracerebral injection of lipopolysaccharide in adult mice. Neurosci Res 70:230-7|
|Tsukamoto, Tomoko; Nakata, Rieko; Tamura, Emi et al. (2010) Vaticanol C, a resveratrol tetramer, activates PPARalpha and PPARbeta/delta in vitro and in vivo. Nutr Metab (Lond) 7:46|
|Guo, Qingmin; Wang, Guangming; Namura, Shobu (2010) Fenofibrate improves cerebral blood flow after middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 30:70-8|
|Wang, Guangming; Liu, Xiaowei; Guo, Qingmin et al. (2010) Chronic treatment with fibrates elevates superoxide dismutase in adult mouse brain microvessels. Brain Res 1359:247-55|
|Wang, Guangming; Guo, Qingmin; Hossain, Mohammed et al. (2009) Bone marrow-derived cells are the major source of MMP-9 contributing to blood-brain barrier dysfunction and infarct formation after ischemic stroke in mice. Brain Res 1294:183-92|
|Guo, Qingmin; Wang, Guangming; Liu, Xiaowei et al. (2009) Effects of gemfibrozil on outcome after permanent middle cerebral artery occlusion in mice. Brain Res 1279:121-30|
|Steele Jr, Ernest C; Guo, Qingmin; Namura, Shobu (2008) Filamentous middle cerebral artery occlusion causes ischemic damage to the retina in mice. Stroke 39:2099-104|