Abstract
Neuronal cell death occurs during many neurodegenerative disorders and stroke. The aberrant, excessive activity of matrix metalloproteinases (MMPs), especially MMP-9, contributes directly to neuron apoptosis and brain damage (Rosenberg et al., 1996; Asahi et al., 2001; Gu et al., 2002; Horstmann et al., 2003). We determined that MMP-9 degrades the extracellular matrix protein laminin and that this degradation induces neuronal apoptosis in a transient focal cerebral ischemia model in mice. We also determined that the highly specific thiirane gelatinase inhibitor SB-3CT blocks MMP-9 activity, including MMP-9-mediated laminin cleavage, thus rescuing neurons from apoptosis. We conclude that MMP-9 is a highly promising drug target and that SB-3CT derivatives have significant therapeutic potential in stroke patients.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects*
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Cerebral Infarction / drug therapy
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Cerebral Infarction / enzymology
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Cerebral Infarction / pathology
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Collagenases / pharmacology
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Drug Administration Schedule
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Drug Evaluation, Preclinical
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Enzyme Precursors / pharmacology
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Heterocyclic Compounds, 1-Ring / administration & dosage
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Heterocyclic Compounds, 1-Ring / pharmacology*
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Heterocyclic Compounds, 1-Ring / therapeutic use
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Infusion Pumps, Implantable
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Ischemic Attack, Transient / drug therapy
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Ischemic Attack, Transient / enzymology*
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Ischemic Attack, Transient / pathology
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Kinetics
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Laminin / metabolism*
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / pharmacology
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Matrix Metalloproteinase 9 / physiology*
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Matrix Metalloproteinase Inhibitors
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Matrix Metalloproteinases / pharmacology
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Matrix Metalloproteinases, Membrane-Associated
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Mice
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Mice, Inbred C57BL
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Neurons / drug effects*
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Neurons / enzymology
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Neurons / pathology
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Protease Inhibitors / administration & dosage
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Protease Inhibitors / pharmacology*
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Protease Inhibitors / therapeutic use
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Reperfusion
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Sulfones / administration & dosage
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Sulfones / pharmacology*
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Sulfones / therapeutic use
Substances
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Enzyme Precursors
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Heterocyclic Compounds, 1-Ring
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Laminin
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Matrix Metalloproteinase Inhibitors
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Protease Inhibitors
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SB 3CT compound
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Sulfones
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Collagenases
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Matrix Metalloproteinases
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Matrix Metalloproteinases, Membrane-Associated
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pro-matrix metalloproteinase 9
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9