Intravenous administration of pravastatin immediately after middle cerebral artery occlusion reduces cerebral oedema in spontaneously hypertensive rats

3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase inhibitors (statins) have been shown to protect against ischemic stroke by mechanisms that are independent of lowering serum cholesterol levels. In this study we investigated the potential neuroprotective effect of a single i.v. treatment with four increasing doses of pravastatin on permanent occlusion ofmiddle cerebral artery (MCAo) in spontaneously hypertensive rats. Pravastatin was given 10 min after MCAo and its effect was determined 24 h later. Treatment results were evaluated in terms of infarct volume, homolateral hemisphere oedema, glial fibrillary acid (GFAP), vimentin (Vim) and endothelial NO synthase (eNOS) immunoreactivity and TUNEL positivity. Cerebral levels of eNOS were measured by western blot analysis. Pravastatin did not reduce cerebral infarct while it mitigated homolateral hemisphere oedema in a dose-dependent manner with respect to controls. No differences among groups were found regarding GFAP and Vim immunoreactivity and TUNEL positivity. Instead, pravastatin treated animals presented a more marked cerebral eNOS immunoreactivity as compared with controls. In agreement with immunohistochemistry, immunoblot revealed dose-dependent increases in cerebral levels of eNOS in pravastatin rats. Our data confirm statin neuroprotection in cerebral ischemia. In particular, it is of great interest that a single i.v. Pravastatin administration reduced cerebral oedema by upregulating eNOS expression/activity. This, by increasing vascular NO bioavailability, could have produced proximal vasodilation and contributed to reducing perfusional deficit. It is worthy stressing how important the anti-oedema action is that pravastatin seems to exert. Indeed, cerebral oedema, when widespread and beyond limits of physiological compensation, causes endocranic hypertension and additional cerebral damage over time