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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


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


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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  1. 1

    rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 333, 1581–1587 (1995).

  2. 2

    Hacke, E.C. et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemisphere stroke. JAMA 274, 1017–1025 (1995).

  3. 3

    Choi, D.W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623–634 (1988).

  4. 4

    Meldrum, B. & Garthwaite, J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends. Pharmacol. Sci. 11, 379–387 (1990).

  5. 5

    Lipton, S.A. & Rosenberg, P.A. Mechanisms of disease: Excitatory amino acids as a final common pathway for neurologic disorders. N. Engl. J. Med. 330, 613–622 (1994).

  6. 6

    Tsirka, S.E., Gualandris, A., Amaral, D.G. & Strickland, S. Excitotoxin-induced neuronal degeneration and seizures are mediated by tissue plasminogen activator. Nature 377, 340–344 (1995).

  7. 7

    Tsirka, S.E., Rogove, A.D. & Strickland, S. Neuronal cell death and tPA. Nature 384, 123–124 (1996).

  8. 8

    Tsirka, S.E., Rogove, A.D., Bugge, T.H., Degen, J.L. & Strickland, S. An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J. Neurosci. 17, 543–552 (1997).

  9. 9

    Longa, E.Z., Weinstein, P.R., Carlson, S. & Cummins, R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20, 84–91 (1989).

  10. 10

    Kinouchi, H. et al. Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc. Natl. Acad. Sci. USA. 88, 11158–11162 (1991).

  11. 11

    Memezawa, H., Smith, M.L. & Siesjö, B.K. Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 23, 552–559 (1992).

  12. 12

    Buchan, A.M., Xue, D. & Slivka, A. A new model of temporary focal neocortical ischemia in the rat. Stroke 23, 273–279 (1992).

  13. 13

    Huang, Z. et al. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265, 1883–1885 (1994).

  14. 14

    Yang, G.Y. & Betz, A.L. Reperfusion-induced injury to the blood-brain barrier after middle cerebral artery occlusion in rats. Stroke 25, 1658–1664 (1994).

  15. 15

    Yang, G. et al. Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia. Stroke 25, 165–170 (1994).

  16. 16

    Kamii, H. et al. Prolonged expression of hsp70 mRNA following transient focal cerebral ischemia in transgenic mice overexpressing CuZn-superoxide dismutase. J. Cereb. Blood Flow Metab. 14, 478–486 (1994).

  17. 17

    Garcia, J.H., Wagner, S., Liu, K.F. & Hu, X.J. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats: Statistical validation. Stroke 26, 627–634 (1995).

  18. 18

    Belayev, L, Busto, R., Zhao, W & Ginsberg, M.D. HU-211, a novel noncompetitive N-methyl-D-aspartate antagonist, improves neurological deficit and reduces infarct volume after reversible focal cerebral ischemia in the rat. Stroke 26, 2313–2320 (1995).

  19. 19

    Connolly, E.S. Jr, Winfree, C.J., Stern, D.M., Solomon, R.A. & Pinsky, D.J. Procedural and strain-related variables significantly affect outcome in a murine model of focal cerebral ischemia. Neurosurgery 18, 523–532 (1996).

  20. 20

    Soriano, S.G. et al. Intercellular adhesion molecule-1 (ICAM-1 )-deficient mice are less susceptible to cerebral ischemia-reperfusion injury. Ann. Neurol. 39, 618–624 (1996).

  21. 21

    Bederson, J.B. et al. Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 17, 472–476 (1986).

  22. 22

    Swanson, R.A. et al. A semiautomated method for measuring brain infarct volume. J. Cereb. Blood Flow Metab. 10, 290–293 (1990).

  23. 23

    Lin, T.-N., He, Y.Y., Wu, G., Khan, M. & Hsu, C.Y. Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke 24, 117–121 (1993).

  24. 24

    Zhang, R.L. et al. Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 44, 1747–1751 (1994).

  25. 25

    Chopp, M. et al. Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 25, 869–876 (1994).

  26. 26

    Sappino, A.-P. et al. Extracellular proteolysis in the adult murine brain. J. Cm. Invest. 92, 679–685 (1993).

  27. 27

    Dirnagl, U., Kaplan, B., Jacewicz, M. & Pulsinelli, W. Continuous measurement of cerebral cortical blood flow by laser Doppler flowmetry in a rat stroke model. J. Cereb. Blood Flow Metab. 9, 589–596 (1989).

  28. 28

    Zhang, F., White, J.G. & ladecola, C. Nitric oxide donors increase blood flow and reduce brain damage in focal ischemia: Evidence that nitric oxide is beneficial in the early stages of cerebral ischemia. J. Cereb. Blood Flow Metab. 14, 217–226 (1994).

  29. 29

    Zhang, F. & g, F. & ladecola, C. Reduction of focal cerebral ischemic damage by delayed treatment with nitric oxide donors. J. Cereb. Blood Flow Metab. 14, 574–580 (1994).

  30. 30

    Rosenberg, G.A., Navratil, M., Barone, F. & Feurstein, G. Proteolytic cascade enzymes increased in focal cerebral ischemia in rat. J. Cereb. Blood Flow Metab. 16, 360–366 (1996).

  31. 31

    Tsirka, S.E., Bugge, T.H., Degen, J.L. & Strickland, S. Neuronal death in the CNS demonstrates a non-fibrin substrate for plasmin. Proc. Natl. Acad. Sci. USA 94, 9779–9781 (1997).

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  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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