Abstract
The upregulation of TIMP-1 following an excitotoxic injury has recently been hypothesized to be part of a general neuronal response that mediates long-lasting changes involved in tissue reorganization and possibly neuroprotection. In this study we have shown for the first time that within hours of applying TIMP-1 in recombinant form or by adenovirus-mediated gene transfer, neurons are highly protected against excitotoxic injury. Neither TIMP-3 nor a nonsecretable form of TIMP-1 protected neurons. TIMP-1 conferred highly significant protection to hippocampal cells exposed to a wide range of glutamic acid concentrations in both dissociated and organotypic hippocampal cultures. TIMP-1 did not prevent apoptotic cell death or death mediated by chemical ischemia. The observed neuroprotection may be explained by a decrease in calcium influx into neurons following stimulation with glutamate. These findings have a fundamental implication for our understanding of the physiological role of secreted TIMP-1 in the central nervous system.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / drug effects
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Brain / metabolism*
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Brain / physiopathology
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Brain Ischemia / drug therapy
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Brain Ischemia / metabolism*
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Brain Ischemia / physiopathology
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Calcium / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / physiology*
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Cell Death / drug effects
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Cell Death / physiology*
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Cells, Cultured
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Glutamic Acid / metabolism*
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Glutamic Acid / pharmacology
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Hippocampus / drug effects
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Hippocampus / metabolism
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Hippocampus / physiopathology
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Matrix Metalloproteinase Inhibitors
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Matrix Metalloproteinases / metabolism
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Nerve Growth Factor / deficiency
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Neurons / drug effects
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Neurons / metabolism*
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Neuroprotective Agents / pharmacology
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Neurotoxins / metabolism
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Organ Culture Techniques
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Potassium Cyanide / pharmacology
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Receptors, Glutamate / drug effects
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Receptors, Glutamate / metabolism
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Recombinant Fusion Proteins / pharmacology
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-1 / metabolism*
Substances
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Enzyme Inhibitors
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Matrix Metalloproteinase Inhibitors
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Neuroprotective Agents
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Neurotoxins
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Receptors, Glutamate
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Recombinant Fusion Proteins
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Tissue Inhibitor of Metalloproteinase-1
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Glutamic Acid
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Nerve Growth Factor
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Matrix Metalloproteinases
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Potassium Cyanide
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Calcium