TISSUE-PLASMINOGEN ACTIVATOR (TPA) INCREASES NEURONAL DAMAGE AFTER FOCAL CEREBRAL-ISCHEMIA IN WILD-TYPE AND TPA-DEFICIENT MICE

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 n eurodegeneration 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 o n cerebral viability during ischemia/reperfusion, we occluded the midd le cerebral artery in wild-type and tPA-deficient mice with an intrava scular filament. This procedure allowed us to examine the role of tPA in ischemia, independent of its effect as a thrombolytic agent. tPA-de ficient mice exhibited similar to 50% smaller cerebral infarcts than w ild-type mice. Intravenous injection of tPA into tPA(-/-) or wild-type mice produced larger infarcts, indicating that tPA can increase strok e-induced injury. Since tPA promotes desirable (thrombolytic) as well as undesirable (neurotoxic) outcomes during stroke, future therapies s hould be aimed at countering the excitotoxic damage of tPA to afford e ven better neuroprotection after an acute cerebral infarct.