Intravenous Rosuvastatin for Acute Stroke Treatment

Abstract

Background and Purpose— Statins exert rapid cholesterol-independent vasoprotective effects. Here, we tested whether postevent treatment with intravenously (i.v.) administered rosuvastatin improves acute stroke outcome in mice. Methods— 129/SV wild-type mice were subjected to 1-hour filamentous middle cerebral artery occlusion (MCAo), followed by reperfusion, and were postevent treated with i.v. or intraperitoneal (i.p.) rosuvastatin given up to 6 hours after MCAo (dose range 0.02 to 20 mg kg −1 body weight). Results— Rosuvastatin, when administered i.v., significantly reduced lesion size when given up to 4 hours after MCAo and in doses as low as 0.2 mg kg −1 . In contrast, i.p. administration provided protection only when given directly on reperfusion at a dose of 20 mg kg −1 but not at lower doses or later time points. Lesion protection was evident as late as 5 days after brain ischemia and was associated with functional improvements in the pole-test and wire-hanging test (2.0 mg kg −1 dose). Neuroprotection with i.v. rosuvastatin was achieved with peak plasma concentrations <0.5 ng ml −1 (ie, with 0.2 mg kg −1 ) and was associated with increased levels of phosphorylated Akt kinase and endothelial nitric oxide synthase in the vasculature. Conclusions— Rosuvastatin, given intravenously at pharmacologically relevant concentrations, protects from focal brain ischemia up to 4 hours after an event. In our opinion, the development of an intravenous statin formulation is warranted for acute stroke trials with statins in humans.