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

Nat Med. 1998 Feb;4(2):228-31. doi: 10.1038/nm0298-228.


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. 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. 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 approximately 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, Differentiation / metabolism
  • Brain / drug effects
  • Brain / pathology
  • Brain Ischemia / drug therapy
  • Brain Ischemia / pathology*
  • Cerebrovascular Circulation
  • Disease Models, Animal
  • Hippocampus / drug effects
  • Hippocampus / pathology
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Microglia / drug effects
  • Neurons / drug effects*
  • Tissue Plasminogen Activator / deficiency*
  • Tissue Plasminogen Activator / metabolism
  • Tissue Plasminogen Activator / pharmacology*


  • Antigens, Differentiation
  • monocyte-macrophage differentiation antigen
  • Tissue Plasminogen Activator