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(Circulation. 2005;112:3486-3494.)
© 2005 American Heart Association, Inc.

Stroke

Multitargeted Effects of Statin-Enhanced Thrombolytic Therapy for Stroke With Recombinant Human Tissue-Type Plasminogen Activator in the Rat

Li Zhang, MD; Zheng Gang Zhang, MD, PhD; Guang Liang Ding, PhD; Quan Jiang, PhD; Xianshuang Liu, MD, PhD; He Meng, MD, PhD; Ann Hozeska, BS; Chunling Zhang, BS; Lian Li, PhD; Dan Morris, MD; Rui Lan Zhang, MD; Mei Lu, PhD; Michael Chopp, PhD

From the Departments of Neurology (L.Z., Z.G.Z., G.L.D., Q.J., X.L., H.M., A.H., C.Z., L.L., R.L.Z., M.C.), Emergency Medicine (D.M.), and Biostatistics and Research Epidemiology (M.L.), Henry Ford Health Sciences Center, Detroit, Mich, and the Department of Physics (M.C.), Oakland University, Rochester, Mich.

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

Received October 25, 2004; revision received September 2, 2005; accepted September 19, 2005.

Background— Microvascular dysfunction posttreatment of stroke with recombinant human tissue-type plasminogen activator (rht-PA) constrains the therapeutic window to 3 hours. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) promote vascular thrombolysis and reduce the inflammation response. We therefore investigated the neuroprotective effects of a combination of atorvastatin and delayed rht-PA treatment in a rat model of embolic stroke.

Methods and Results— Rats subjected to embolic middle cerebral artery occlusion were treated with atorvastatin in combination with rht-PA 4 hours after stroke. Magnetic resonance imaging measurements revealed that combination treatment with atorvastatin and rht-PA blocked the expansion of the ischemic lesion, which improved neurological function compared with saline-treated rats. Real-time reverse transcription–polymerase chain reaction analysis of single endothelial cells isolated by laser-capture microdissection from brain tissue and immunostaining showed that combination treatment downregulated expression of tissue factor, von Willebrand factor, protease-activated receptor-1, intercellular adhesion molecule-1, and matrix metalloproteinase-9, which concomitantly reduced cerebral microvascular thrombosis and enhanced microvascular integrity. Combination treatment did not increase cerebrovascular endothelial nitric oxide synthase (eNOS) levels or eNOS activity, and inhibition of NOS activity with N-nitro-L-arginine methyl ester did not block the beneficial effects of combination treatment on stroke. Furthermore, combination treatment compared with thrombolytic monotherapy increased cerebral blood flow and reduced infarct volume in eNOS-null mice.

Conclusions— These data demonstrate that combination treatment with atorvastatin and rht-PA exerts a neuroprotective effect when administered 4 hours after stroke and that the therapeutic benefits are likely attributed to its multitargeted effects on cerebrovascular patency and integrity.

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