Tissue plasminogen activator extravasated through the cerebral vessels

Tadashi Harada; Tsuneo Kano; Yoichi Katayama; Toshinori Matsuzaki; Emiri Tejima; Morimichi Koshinaga

doi:10.1160/TH05-03-0164

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(04): 791-796
DOI: 10.1160/TH05-03-0164

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Tissue plasminogen activator extravasated through the cerebral vessels

Evaluation using a rat thromboembolic stroke model

Tadashi Harada

¹Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan

,

Tsuneo Kano

¹Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan

,

Yoichi Katayama

¹Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan

,

Toshinori Matsuzaki

¹Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan

,

Emiri Tejima

¹Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan

,

Morimichi Koshinaga

¹Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan

› Author Affiliations

Abstract

Summary

Neurotoxic effects of endogenous tissue plasminogen activator (tPA) have recently been reported. Employing a rat model of thromboembolic stroke, we evaluated the extent and degree of extravasation of exogenous tPA administered for the purpose of fibrinolysis. In a thromboembolic model using Sprague-Dawley rats, focal cerebral ischemia was induced at the territory of the middle cerebral artery (MCA). Early reperfusion was induced by administering tPA (10 mg/kg) intravenously at 30 minutes after the onset of ischemia. Extravasated tPA was evaluated by immunohistochemistry, and the concentration of tPA in the brain tissue was quantified by enzyme-linked immunosorbent assay methods. The integrity of the blood-brain barrier (BBB) was examined electronmicroscopically. In a thread model of transient ischemia, reperfusion was induced without tPA adminis-tration at 30 minutes or 2 hours after the onset of ischemia, and the tPA content of the brain was quantified. In the rats with thromboembolic stroke, extravasation of tPA was observed at the territory of the MCA. Both the endogenous and exogenous tPA contents were 3.5±1.6 ng/ml of homogenized brain in saline. Electronmicroscopically, mild ischemic changes were observed, although the integrity of the BBB was preserved. In the thread model rats, the endogenous tPA contents of the ischemic hemisphere were 0.9±0.1 and 1.0±0.2 ng/ml in the 30-minute and 2-hour ischemia groups, respectively, and were significantly lower than the tPA contents in the thromboembolic stroke rats (p < 0.01). The present findings indicate that significant extravasation of exogenous tPA occurs through the cerebral vessels even though early reperfusion is induced.

Keywords

Extravasation - fibrinolysis - rat - thromboembolic stroke - tissue plasminogen activator

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References

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