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Efficacy of intra-arterial and intravenous prourokinase in an embolic stroke model evaluated by diffusion-perfusion magnetic resonance imaging

From the Department of Neurology (Drs. Takano, Fisher, and Tatlisumak), Memorial Health Care; Departments of Neurology and Radiology (Dr. Fisher), The University of Massachusetts Medical School; Department of Biomedical Engineering (R.A.D. Carano, M. Meiler, and Dr. Sotak), Worcester Polytechnical Institute, Worcester, MA; Department of Neurology (Dr. Tatlisumak), Helsinki University Central Hospital, Helsinki, Finland; and Abbott Laboratories (Dr. Kleinert), Abbott Park, IL.

Address correspondence and reprint requests to Dr. Marc Fisher, Memorial Health Care, 119 Belmont Street, Worcester, MA 01605.

Objective: To explore the utility of intravenous (IV) prourokinase treatment, we compared intra-arterial (IA) and IV delivery in a rat embolic stroke model, using diffusion (DWI) and perfusion (PI) magnetic resonance imaging to assess in vivo effects on ischemic lesion evolution and reperfusion.

Background: Thrombolytic therapy with recombinant tissue-type plasminogen activator(rt-PA) for acute ischemic stroke is useful during the initial hours after onset. Prourokinase is a novel thrombolytic agent with potential safety advantages in comparison to rt-PA.

Methods: Twenty-four male Sprague-Dawley rats were embolized with autologous blood clots into the middle cerebral artery territory and then randomly assigned at 30 minutes after embolization to a 2-hour bolus infusion with IA prourokinase, IV prourokinase, or vehicle. DWI and PI were performed before treatment and repeated during and at the end of the treatment.

Results: PI demonstrated that both IA and IV significantly improved the percentage of the ischemic hemisphere that was normally perfused when the 20-minute, pretreatment, and 145-minute after embolization time points were compared; in the control group, the hypoperfused volume increased over time. DWI disclosed that the ischemic lesion evolution slightly decreased in the IA group, remained stable in the IV group, and increased over time in the control group. Infarct volume by triphenyltetrazolium chloride (TTC) staining was significantly smaller in both treatment groups than controls.

Conclusions: These results demonstrate that IA and IV therapy with prourokinase are equally effective in promoting reperfusion and inhibiting the development of focal ischemic injury in this rat embolic stroke model.

Supported in part by an Established Investigator Award from the American Heart Association (C.H.S.) and by Abbott Pharmaceuticals.

Received March 17, 1997. Accepted in final form October 9, 1997.

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