Stroke is a major cause of morbidity and mortality whose treatment options are limited. We present preliminary data indicating that chronic inhibition of the pathway leading to cholesterol synthesis decreases infarct size following MCA occlusion in normocholesterolemic mice by a mechanism related primarily to eNOS up-regulation. The goals of this proposal are to clarify and characterize the molecular and physiological effects of chronic statin administration (HMG-CoA reductase inhibition) on eNOS regulation, cerebral blood flow (CBF), and infarct size, as well as to determine the relevance of this pathway to stroke prophylaxis. After optimizing conditions for protection of measuring cerebral blood flow at rest and during MCA occlusion using indicator fractionation and functional imaging techniques. Preliminary data indicate that both infarct sparing and augmented cerebral blood flow observed in the wild type mouse are absent in mice deficient in eNOS gene expression (eNOS knockout mice). To explore molecular mechanisms of action, we propose to identify in vitro the specific step(s) in the cascade from HMG-CoA to cholesterol (so-called mevalonate pathway) responsible for eNOS up- regulation [e.g. geranylgeranyl, farnesyl, etc., and downstream factors (e.g., rho, ras)]. Potentially, steps in the pathway may then be identified which specifically promote endothelial up-regulation of eNOS without cholesterol-lowering. Because stains induce eNOS expression within blood vessels, we also propose to evaluate cerebral blood flow responses to hypercapnia, metabolism-coupling and auto-regulation, and pharmacological responses of pial vessels to superfused endothelium and non-endothelium dependent vasodilators (e.g. acetylcholine and papaverine). Because L-arginine is an eNOS substrate and because L- arginine infusion normally increases rCBF and vascular diameter, we propose to examine whether the pharmacological response to this amino acid can be enhance after chronic statin treatment, particularly after MCA occlusion. Taken together, we propose to combine molecular techniques with animal physiology and knockout strategies to examine specific hypotheses concerning a promising a novel prophylactic treatment strategy for stroke.
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