Objective—We tested the hypothesis that the phosphatidylinositol-3 kinase (PI3K)/Akt pathway mediates the neuroprotective effect of combination therapy of atorvastatin and tissue-type plasminogen activator (tPA) in rats after stroke.

Methods and Results—Combination of atorvastatin (20 mg/kg) and tPA (10 mg/kg) significantly reduced ischemic lesion volume, whereas monotherapy with atorvastatin and tPA did not reduce the lesion volume, when the treatments were initiated 4 hours after embolic middle cerebral artery occlusion (MCAo). Western blot analysis revealed that treatment with atorvastatin alone and in combination treatment with tPA significantly increased Akt phosphorylation compared with treatment with saline and tPA alone. Inhibition of the PI3K/Akt pathway with wortmannin completely abolished the reduction of lesion volume afforded by combination of atorvastatin and tPA. Real-time RT-PCR analysis of cerebral endothelial cells isolated by laser-capture microdissection from the ischemic boundary region showed that MCAo upregulated early growth response 1 (Egr-1) and vascular endothelial growth factor (VEGF) mRNA levels and tPA monotherapy further increased Egr-1 and VEGF mRNA levels. However, combination of atorvastatin and tPA significantly suppressed Egr-1 and VEGF mRNA levels in cerebral endothelial cells.

Conclusions—Activation of Akt and downregulation of cerebral endothelial Egr-1 and VEGF gene expression by atorvastatin contribute to the neuroprotective effect of combination treatment with atorvastatin and tPA.