Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice

Background and Purpose-The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) lower serum cholesterol and decrease the inc idence of stroke and cardiovascular disease. There is growing evidence that statins exert some of their beneficial effects independent of cholesterol lowering. Indeed, we have previously demonstrated that chronic simvastatin administration upregulates endothelial nitric oxide synthase (eNOS), result ing in more functional protein, augmentation of cerebral blood flow, and ne uroprotection in a murine model of cerebral ischemia. In this report we exa mined whether another member of the statin family shared these effects and whether eNOS upregulation is sustained with longer treatment. Methods-Mevastatin (2 mg/kg or 20 mg/kg per day) was administered to 18- to 22-g male mice for 7, 14, or 28 days before 2-hour middle cerebral artery occlusion with the use of the filament model (n = 9 to 12). Neurological de ficits and cerebral infarct volumes were assessed at 24 hours. Arterial blo od pressure and gases, relative cerebral blood flow, and blood cholesterol levels were monitored in a subset of animals (n=5). Absolute cerebral blood flow was measured by the [C-14]iodoamphetamine indicator fractionation tec hnique (n=6), eNOS mRNA and protein levels were determined. Results-Mevastatin increased levels of eNOS mRNA and protein, reduced infar ct size, and improved neurological deficits in a dose- and time-dependent m anner. Greatest protection was seen with 13- and 25-day high-dose treatment (26% and 37% infarct reduction, respectively). Cholesterol levels were red uced only after 28 days of treatment and did not correlate with infarct red uction. Baseline absolute cerebral blood flow was 30% higher after 14-day h igh-dose treatment. Conclusions-Chronic prophylactic treatment with mevastatin upregulated eNOS and augmented cerebral blood flow. These changes occurred in the absence o f changes in serum cholesterol levels, were sustained for up to 1 month of treatment, and resulted in neuroprotection after middle cerebral artery occ lusion.