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Recombinant tissue plasminogen activator induces blood–brain barrier breakdown by a matrix metalloproteinase-9-independent pathway after transient focal cerebral ischemia in mouse

Authors

  • Jean-Christophe Copin,

    1. Division of Neurosurgery, University Hospitals of Geneva, Geneva, Switzerland
    2. Division of Intensive Care, University Hospitals of Geneva, Geneva, Switzerland
    3. Geneva Neuroscience Center, University of Geneva, Geneva, Switzerland
    4. Centre Médical Universitaire, 1 rue Michel Servet, CH-1211 Genève 4, Switzerland
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  • Daniel Jiménez Bengualid,

    1. Division of Intensive Care, University Hospitals of Geneva, Geneva, Switzerland
    2. Geneva Neuroscience Center, University of Geneva, Geneva, Switzerland
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  • Rafaela F. Da Silva,

    1. Institute of Bioengineering, Swiss Federal Institute of Technology, Lausanne, Switzerland
    2. Department of Physiology, Federal University of Minas Gerais, Belo Horizonte, Brazil
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  • Odysseas Kargiotis,

    1. Division of Intensive Care, University Hospitals of Geneva, Geneva, Switzerland
    2. Division of Neurology, University Hospitals of Geneva, Geneva, Switzerland
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  • Karl Schaller,

    1. Division of Neurosurgery, University Hospitals of Geneva, Geneva, Switzerland
    2. Geneva Neuroscience Center, University of Geneva, Geneva, Switzerland
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  • Yvan Gasche

    1. Division of Intensive Care, University Hospitals of Geneva, Geneva, Switzerland
    2. Geneva Neuroscience Center, University of Geneva, Geneva, Switzerland
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Dr Jean-Christophe Copin, 4Centre Médical Universitaire, as above.
E-mail: jean-christophe.copin@unige.ch

Abstract

The role of the inducible matrix metalloproteinase (MMP)-9 in blood–brain barrier (BBB) disruption after ischemic stroke is well accepted. Recombinant tissue plasminogen activator (r-tPA) is the only approved thrombolytic treatment of ischemic stroke but r-tPA is potentially neurotoxic. Vasogenic edema after r-tPA treatment has been linked with an increase in cerebral MMP-9. However, because cerebral ischemia clearly increases the levels of endogenous tPA, the consequence of additional r-tPA may be questionable. In this study, wild type and MMP-9 knockout mice were subjected to 90 min transient middle cerebral artery occlusion and treated with 10 mg/kg r-tPA. At 24 h after occlusion, BBB permeability, hemispheric enlargement, collagen and laminin degradation as well as cerebral infarction were increased in both wild type and MMP-9 knockout treated animals as compared with non-treated animals. Mortality was increased in wild type but reduced in knockout treated mice. Cerebral MMP-9 concentration was not modified by r-tPA. However, pre-treatment with p-aminobenzoyl-gly-pro-D-leu-D-ala-hydroxamate, a broad-spectrum MMP inhibitor, counteracted the effects of r-tPA on the neurovascular unit and decreased mortality in both wild type and knockout mice. MMP inhibition did not modify cerebral infarction in r-tPA-treated animals. Our results suggest that r-tPA toxicity is mainly independent of MMP-9 after transient middle cerebral artery occlusion but could involve some other MMPs. Additionally, our results support the hypothesis of a dissociation between r-tPA-dependent mechanisms of BBB breakdown and cerebral infarction. Due to the importance of r-tPA in thrombolytic treatment of ischemic stroke patients, the MMPs that could participate in r-tPA-induced BBB disruption should be further characterized.

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