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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2470.)
© 2007 American Heart Association, Inc.

Thrombosis

The PI3K/Akt Pathway Mediates the Neuroprotective Effect of Atorvastatin in Extending Thrombolytic Therapy After Embolic Stroke in the Rat

Li Zhang; Zheng Gang Zhang; Xian Shuang Liu; Ann Hozeska-Solgot; Michael Chopp

From the Department of Neurology (L.Z., Z.G.Z., X.S.L., A.H.S. M.C.), Henry Ford Health System, Detroit, MI; and the Department of Physics (M.C.), Oakland University, Rochester, Minn.

Correspondence to Zheng Gang Zhang, MD, PhD, Henry Ford Health System, Department of Neurology, 2799 West Grand Blvd, Detroit, MI 48202. E-mail zhazh{at}neuro.hfh.edu

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.

Combination treatment with atorvastatin and tPA 4h after embolic stroke substantially reduced infarct volume and activated Akt. Blockage of the PI3K/Akt pathway with wortmannin completely abolished the neuroprotective effect of the combination therapy. These data indicate that the PI3K/Akt pathway mediates the neuroprotective effects of atorvastatin.

Key Words: stroke • tissue • plasminogen activator • atorvastatin

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