Vascular protection with atorvastatin after acute ischemic stroke in diabetes

Abstract

Ischemic stroke is a leading cause of death and disability in the United States and diabetes mellitus is the fastest growing risk factor for stroke. In addition, hyperglycemia, which is usually associated with diabetes, tends to worsen ischemia/reperfusion injury and to induce more oxidative stress damage. Our laboratory has shown that type II diabetic animals (Goto-Kakizaki rats (GKs) are more susceptible to vascular damage after experimental cerebral ischemia than non-diabetic animals. This made GKs a good model to test vascular protective agents after acute ischemic stroke. Statins possess neurovascular protective properties even when administered after the onset of ischemia. However, the acute vascular effects of statins after ischemic stroke in diabetes have not been studied to date. The goal of these studies was to evaluate the efficacy and magnitude of vascular protection of acute statin therapy in both GKs and their normoglycemic controls after experimental ischemic stroke. I hypothesized that acute atorvastatin treatment after stroke will be vascular protective in both diabetic rats (GKs) and normoglycemic controls (Wistar rats) through the reduction of oxidative stress and restoration of nitric oxide (NO). I investigated the hemorrhagic transformation, infarct size and neurobehavioral outcome in rats subjected to 3 hours of middle cerebral artery occlusion (MCAo) followed by 21 hours reperfusion. I also investigated the different biomarkers and the plasma concentration involved with atorvastatin neurovascular protection. Results presented in this dissertation show that atorvastatin 30 mg/Kg/day is neurovascular protective after stroke in both normoglycemic and diabetic rats and improves neurobehavioral outcomes. The Phospho-inositol-3-kinase (PI3K)/Akt phosphorylation pathway was found to be involved in the protective effects of atorvastatin. However, atorvastatin did not have an effect on oxidative stress markers or endothelial nitric oxide synthase (eNOS) expression and its phosphorylation in these studies. Neurovascular protection with atorvastatin in rats was achieved at a safe plasma concentration, similar to that seen after 80 mg/day of atorvastatin in humans.