Reduction of Tissue Plasminogen Activator-Induced Hemorrhage and Brain Injury by Free Radical Spin Trapping After Embolic Focal Cerebral Ischemia in Rats

• Published in: Journal of cerebral blood flow and metabolism 2000-03, Vol.20 (3), p.452-457
• Main Authors: Asahi, Minoru, Asahi, Kazuko, Wang, Xiaoying, Lo, Eng H.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain - pathology; Brain Ischemia - drug therapy; Brain Ischemia - therapy; Cerebral Hemorrhage - chemically induced; Cerebral Hemorrhage - complications; Cerebral Hemorrhage - etiology; Cyclic N-Oxides; Drug Therapy, Combination; Drug toxicity and drugs side effects treatment; Free Radicals; Hypertension - complications; Intracranial Embolism - drug therapy; Intracranial Embolism - therapy; Male; Medical sciences; Nitrogen Oxides - therapeutic use; Pharmacology. Drug treatments; Plasminogen Activators - adverse effects; Plasminogen Activators - therapeutic use; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reperfusion Injury - complications; Spin Trapping; Tissue Plasminogen Activator - adverse effects; Tissue Plasminogen Activator - therapeutic use; Toxicity: nervous system and muscle
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1097/00004647-200003000-00002

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) remains complicated by serious risks of cerebral hemorrhage and brain injury. In this study, a novel model of tPA-induced hemorrhage was used in spontaneously hypertensive rats to examine the correlates of hemorrhage, and test methods of reducing hemorrhage and brain injury. Homologous blood clot emboli were used to occlude the middle cerebral artery in spontaneously hypertensive rats, and delayed administration of tPA (6 hours postischemia) resulted in high rates of cerebral hemorrhage 24 hours later. Compared with untreated rats, tPA significantly increased hemorrhage volumes by almost 85%. Concomitantly, infarction and neurological deficits were worsened by tPA. A parallel experiment in normotensive Wistar-Kyoto rats showed markedly reduced rates of hemorrhage, and tPA did not significantly increase hemorrhage volumes. To examine whether tPA-induced hemorrhage was caused by the delayed onset of reperfusion per se, another group of spontaneously hypertensive rats was subjected to focal ischemia using a mechanical method of arterial occlusion. Delayed (6 hours) reperfusion via mechanical means did not induce hemorrhage. However, administration of tPA plus delayed mechanical reperfusion significantly increased hemorrhage volumes. Since reperfusion injury was implicated, a final experiment compared outcomes in spontaneously hypertensive rats treated with tPA plus the free radical spin trap α-phenyl tert butyl nitrone (α-PBN) versus tPA alone. tPA-induced hemorrhage volumes were reduced by 40% with α-PBN, and infarction and neurological deficits were also decreased. These results indicate that (1) blood pressure isanimportant correlate of tPA-induced hemorrhage, (2) tPA interacts negatively with reperfusion injury to promote hemorrhage, and (3) combination therapies with anti-free radical treatments may reduce the severity of tPA-induced hemorrhage and brain injury after cerebral ischemia.