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Role of matrix metalloproteinases in apoptosis after transient focal cerebral ischemia in rats and mice

Authors

  • Jean-Christophe Copin,

    1. Department of Neuroscience, University Medical Center, 1211 Geneva, Switzerland
    2. Department of Anaesthesiology, Pharmacology and Surgical Intensive Care, University Medical Center, 1211 Geneva, Switzerland
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  • Marie-Christelle Goodyear,

    1. Department of Neuroscience, University Medical Center, 1211 Geneva, Switzerland
    2. Department of Anaesthesiology, Pharmacology and Surgical Intensive Care, University Medical Center, 1211 Geneva, Switzerland
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  • Jeffrey M. Gidday,

    1. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • Aarti R. Shah,

    1. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • Eduardo Gascon,

    1. Department of Neuroscience, University Medical Center, 1211 Geneva, Switzerland
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  • Alexandre Dayer,

    1. Department of Neuroscience, University Medical Center, 1211 Geneva, Switzerland
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  • Denis M. Morel,

    1. Department of Anaesthesiology, Pharmacology and Surgical Intensive Care, University Medical Center, 1211 Geneva, Switzerland
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  • Yvan Gasche

    1. Department of Neuroscience, University Medical Center, 1211 Geneva, Switzerland
    2. Department of Anaesthesiology, Pharmacology and Surgical Intensive Care, University Medical Center, 1211 Geneva, Switzerland
    3. Department of Internal Medicine, University Medical Center, 1211 Geneva, Switzerland
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Dr J.-C. Copin, 2Department of Anaesthesiology, as above.
E-mail: Jean-Christophe.Copin@medecine.unige.ch

Abstract

The involvement of matrix metalloproteinases (MMPs) in cerebral ischemia-induced apoptosis was investigated in a model of transient focal cerebral ischemia in rats treated intracerebroventricularly (i.c.v.) with 4-((3-(4-phenoxylphenoxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylic acid N-hydroxy amide, a broad spectrum non-peptidic hydroxamic acid MMP inhibitor, and in MMP-9-deficient mice. Our results showed that MMP inhibition reduced DNA fragmentation by 51% (< 0.001) and cerebral infarct by 60% (P < 0.05) after ischemia. This protection was concomitant with a 29% reduction of cytochrome c release into the cytosol (< 0.005) and a 54% reduction of calpain-related α-spectrin degradation (< 0.05), as well as with an 84% increase in the immunoreactive signal of the native form of poly(ADP) ribose polymerase (< 0.01). By contrast, specific targeting of the mmp9 gene in mice did reduce cerebral damage by 34% (P < 0.05) but did not modify the apoptotic response after cerebral ischemia. However, i.c.v. injection of MMP-9-deficient mice with the same broad-spectrum inhibitor used in rats significantly reduced DNA degradation by 32% (P < 0.05) and contributed even further to the protection of the ischemic brain. Together, our pharmacological and genetic results indicate that MMPs other than MMP-9 are actively involved in cerebral ischemia-induced apoptosis.

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