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

Nature Medicinevolume 4pages228231 (1998) | Download Citation

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  • An Erratum to this article was published on 01 May 1998

Abstract

Intravenous tissue plasminogen activator (tPA) is used to treat acute stroke because of its thrombolytic activity and its ability to restore circulation to the brain1,2. 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 excitotoxins3–8. 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 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 neuropro-tection after an acute cerebral infarct.

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Affiliations

  1. Cerebrovascular and NeuroScience Research Institute, Brigham and Women's Hospital/Harvard Medical School, 221 Longwood Avenue, LMRC First Floor, Boston, Massachusetts, 02115, USA

    • Yanming F. Wang
    • , Philip E. Stieg
    •  & Stuart A. Lipton
  2. Neurosurgery, Children's Hospital and Brigham and Women's Hospital, 300 Longwood Avenue, 75 Francis Street, Boston, Massachusetts, 02115, USA

    • Yanming F. Wang
    • , Philip E. Stieg
    •  & Stuart A. Lipton
  3. Anesthesiology Services, Children's Hospital and Brigham and Women's Hospital, 300 Longwood Avenue, 75 Francis Street, Boston, Massachusetts, 02115, USA

    • Sulpicio G. Soriano
  4. Program in Neuroscience, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts, 02115, USA

    • Yanming F. Wang
    • , Philip E. Stieg
    •  & Stuart A. Lipton
  5. Department of Pharmacology, BST, T8, Room 125, University Medical Center at Stony Brook, Stony Brook, New York, 11794, USA

    • Stella E. Tsirka
    •  & Sidney Strickland

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https://doi.org/10.1038/nm0298-228

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