Early Atorvastatin Reduces Hemorrhage after Acute Cerebral Ischemia in Diabetic Rats

Abstract

Ischemic stroke is a leading cause of death in the United States, and diabetes mellitus is a major risk factor for stroke. Our previous work showed that type II diabetic rats [Goto-Kakizaki (GK)] have more bleeding after stroke than their normoglycemic controls (Wistar). Our aim was to evaluate the vascular protective properties of acute atorvastatin therapy after experimental ischemic stroke in diabetes and to explore the effect of stroke in GK rats compared with their normoglycemic controls. Fifty male Wistar and 40 GK rats (270-305 g) underwent 3 h of middle cerebral artery occlusion followed by reperfusion for 21 h. Animals received atorvastatin (5 mg/kg), atorvastatin (15 mg/kg), or vehicle, administered by oral gavage, one dose 5 min after reperfusion and a second dose after 12 h. At 24 h, functional outcome was measured, and brain tissue was analyzed for infarct volume, hemoglobin content, and molecular biomarkers. Plasma was collected for analysis of atorvastatin concentrations. Atorvastatin-treated groups had significantly lower bleeding rates (p = 0.0011) and infarct volume (p = 0.0007) compared with controls. There was a significant reduction in hemoglobin content and infarct volume only in the higher dose group (15 mg/kg) (p < 0.05), and these benefits were more than 4 times greater in the diabetic animals. Atorvastatin (15 mg/kg) improved neurological outcome in both Wistar and GK rats (p = 0.029) at a peak concentration of 27 to 77 ng/ml and was associated with an increase in Akt phosphorylation (p = 0.0007). We concluded that atorvastatin is a vascular protective agent after experimental ischemic stroke, especially in diabetes.