Abstract
Cerebral cortical neurons have a heightened sensitivity to hypoxia and their survival depends on their ability to accommodate to changes in the concentration of oxygen in their environment. Tissue-type plasminogen activator (tPA) is a serine proteinase that activates the zymogen plasminogen into plasmin. Hypoxia induces the release of tPA from cerebral cortical neurons, and it has been proposed that tPA mediates hypoxic and ischemic neuronal death. Here, we show that tPA is devoid of neurotoxic effects and instead is an endogenous neuroprotectant that renders neurons resistant to the effects of lethal hypoxia and ischemia. We present in vitro and in vivo evidence indicating that endogenous tPA and recombinant tPA induce the expression of neuronal tumor necrosis factor-α. This effect, mediated by plasmin and the N-methyl-D-aspartate receptor, leads to increased expression of the cyclin-dependent kinase inhibitor p21 and p21-mediated development of early hypoxic and ischemic tolerance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Death / drug effects
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p21 / physiology
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Enzyme-Linked Immunosorbent Assay
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Hypoxia-Ischemia, Brain / drug therapy
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Hypoxia-Ischemia, Brain / metabolism*
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Hypoxia-Ischemia, Brain / pathology
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Ischemic Preconditioning
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neurons / drug effects
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Neurons / metabolism*
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Neurons / pathology
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use
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Reverse Transcriptase Polymerase Chain Reaction
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Tissue Plasminogen Activator / genetics
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Tissue Plasminogen Activator / pharmacology
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Tissue Plasminogen Activator / physiology*
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Tissue Plasminogen Activator / therapeutic use
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / physiology*
Substances
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Cyclin-Dependent Kinase Inhibitor p21
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Neuroprotective Agents
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Tumor Necrosis Factor-alpha
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Tissue Plasminogen Activator