Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice

被引:554
作者
Wang, YMF
Tsirka, SE
Strickland, S
Stieg, PE
Soriano, SG
Lipton, SA
机构
[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cerebrovasc & Neurosci Res Inst, Boston, MA 02115 USA
[2] Childrens Hosp, Neurosurg Serv, Boston, MA 02115 USA
[3] Childrens Hosp, Anesthesiol Serv, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA
[5] SUNY Stony Brook, Med Ctr, Dept Pharmacol, Stony Brook, NY 11794 USA
关键词
D O I
10.1038/nm0298-228
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Intravenous tissue plasminogen activator (tPA) is used to treat acute stroke because of its thrombolytic activity and its ability to restore circulation to the brain(1,2). However, this protease also promotes neurodegeneration after intracerebral injection of excitotoxins such as glutamate, and neuronal damage after a cerebral infarct is thought to be mediated by excitotoxins(3-8). To investigate the effects of tPA on cerebral viability during ischemia/reperfusion, we occluded the middle cerebral artery in wild-type and tPA-deficient mice with an intravascular filament. This procedure allowed us to examine the role of tPA in ischemia, independent of its effect as a thrombolytic agent. tPA-deficient mice exhibited similar to 50% smaller cerebral infarcts than wild-type mice. Intravenous injection of tPA into tPA(-/-) or wild-type mice produced larger infarcts, indicating that tPA can increase stroke-induced injury. Since tPA promotes desirable (thrombolytic) as well as undesirable (neurotoxic) outcomes during stroke, future therapies should be aimed at countering the excitotoxic damage of tPA to afford even better neuroprotection after an acute cerebral infarct.
引用
收藏
页码:228 / 231
页数:4
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