Smad3-dependent induction of plasminogen activator inhibitor-1 in astrocytes mediates neuroprotective activity of transforming growth factor-beta 1 against NMDA-induced necrosis.

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.

• Authors: Fabian Docagne, Olivier Nicole, Cecilia Gabriel, Mónica Fernández-Monreal, Sylvain Lesné, Carine Ali, Laurent Plawinski, Peter Carmeliet, Eric T MacKenzie, Alain Buisson, Denis Vivien
• Journal: Molecular and cellular neurosciences (Mol Cell Neurosci) Vol. 21 Issue 4 Pg. 634-44 (Dec 2002) ISSN: 1044-7431 [Print] United States
• PMID: 12504596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Excitatory Amino Acid Antagonists
• Neuroprotective Agents
• Neurotoxins
• Plasminogen Activator Inhibitor 1
• Recombinant Fusion Proteins
• Smad3 Protein
• Smad3 protein, mouse
• Tgfb1 protein, mouse
• Trans-Activators
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• N-Methylaspartate
• Tissue Plasminogen Activator

Topics

• Animals
• Animals, Newborn
• Astrocytes (drug effects, metabolism)
• Brain (drug effects, metabolism, physiopathology)
• Calcium Signaling (drug effects, physiology)
• Cells, Cultured
• Coculture Techniques
• DNA-Binding Proteins (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Antagonists (pharmacology)
• Fetus
• Mice
• N-Methylaspartate (antagonists & inhibitors)
• Nerve Degeneration (chemically induced, drug therapy, metabolism)
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (metabolism, pharmacology)
• Neurotoxins (antagonists & inhibitors)
• Plasminogen Activator Inhibitor 1 (genetics, metabolism, pharmacology)
• Recombinant Fusion Proteins
• Smad3 Protein
• Stroke (drug therapy, metabolism, physiopathology)
• Tissue Plasminogen Activator (antagonists & inhibitors, therapeutic use, toxicity)
• Trans-Activators (drug effects, metabolism)
• Transforming Growth Factor beta (metabolism, pharmacology)
• Transforming Growth Factor beta1