Smad3-dependent induction of plasminogen activator inhibitor-1 in astrocytes mediates neuroprotective activity of transforming growth factor-β1 against NMDA-induced necrosis

Fabian Docagne, Olivier Nicole, Cecilia Gabriel, Mónica Fernández-Monreal, Sylvain Lesné, Carine Ali, Laurent Plawinski, Peter Carmeliet, Eric T. MacKenzie, Alain Buisson, Denis Vivien

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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-β1 and focused on the transduction pathway involved in this effect. We demonstrated that PAI-1, produced by astrocytes, mediates the neuroprotective activity of TGF-β1 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-β-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.

Original languageEnglish (US)
Pages (from-to)634-644
Number of pages11
JournalMolecular and Cellular Neuroscience
Volume21
Issue number4
DOIs
StatePublished - 2002

Keywords

  • Calcium
  • Excitotoxicity
  • NMDA
  • PAI-1
  • Smad
  • TGF
  • t-PA

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