Abstract
The intravenous injection of the serine protease, tissue-type plasminogen activator (t-PA), has shown to benefit stroke patients by promoting early reperfusion. However, it has recently been suggested that t-PA activity, in the cerebral parenchyma, may also potentiate excitotoxic neuronal death. The present study has dealt with the role of the t-PA inhibitor, PAI-1, in the neuroprotective activity of the cytokine TGF-beta1 and focused on the transduction pathway involved in this effect. We demonstrated that PAI-1, produced by astrocytes, mediates the neuroprotective activity of TGF-beta 1 against N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. This t-PA inhibitor, PAI-1, protected neurons against NMDA-induced neuronal death by modulating the NMDA-evoked calcium influx. Finally, we showed that the activation of the Smad3-dependent transduction pathway mediates the TGF-beta-induced up-regulation of PAI-1 and subsequent neuroprotection. Overall, this study underlines the critical role of the t-PA/PAI-1 axis in the regulation of glutamatergic neurotransmission.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Astrocytes / drug effects*
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Astrocytes / metabolism
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Brain / drug effects
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Brain / metabolism
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Brain / physiopathology
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Calcium Signaling / drug effects
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Calcium Signaling / physiology
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Cells, Cultured
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Coculture Techniques
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / metabolism*
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Dose-Response Relationship, Drug
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Excitatory Amino Acid Antagonists / pharmacology
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Fetus
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Mice
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N-Methylaspartate / antagonists & inhibitors*
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Nerve Degeneration / chemically induced
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Nerve Degeneration / drug therapy
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Nerve Degeneration / metabolism
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Neurons / drug effects
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Neurons / metabolism
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Neuroprotective Agents / metabolism*
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Neuroprotective Agents / pharmacology
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Neurotoxins / antagonists & inhibitors*
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Plasminogen Activator Inhibitor 1 / genetics
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Plasminogen Activator Inhibitor 1 / metabolism*
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Plasminogen Activator Inhibitor 1 / pharmacology
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Recombinant Fusion Proteins
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Smad3 Protein
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Stroke / drug therapy
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Stroke / metabolism
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Stroke / physiopathology
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Tissue Plasminogen Activator / antagonists & inhibitors
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Tissue Plasminogen Activator / therapeutic use
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Tissue Plasminogen Activator / toxicity
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Trans-Activators / drug effects
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Trans-Activators / metabolism*
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta / pharmacology
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Transforming Growth Factor beta1
Substances
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DNA-Binding Proteins
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Excitatory Amino Acid Antagonists
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Neuroprotective Agents
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Neurotoxins
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Plasminogen Activator Inhibitor 1
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Recombinant Fusion Proteins
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Smad3 Protein
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Smad3 protein, mouse
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Tgfb1 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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N-Methylaspartate
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Tissue Plasminogen Activator