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
alpha-phenyl tert butyl nitrone (
alpha-PBN) versus tPA alone. tPA-induced
hemorrhage volumes were reduced by 40% with
alpha-PBN, and
infarction and neurological deficits were also decreased. These results indicate that (1) blood pressure is an important 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.