Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo

Amandine Jullienne, Axel Montagne, Cyrille Orset, Flavie Lesept, David E. Jane, Daniel T. Monaghan, Eric Maubert, Denis Vivien, Carine Ali

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: Tissue plasminogen activator (tPA) exerts multiple functions in the central nervous system, depending on the partner with which it interacts. In particular, tPA acts as a positive neuromodulator of N-methyl-D-aspartate glutamatergic receptors (NMDAR). At the molecular level, it has been proposed that the pro-neurotoxicity mediated by tPA might occur through extrasynaptic NMDAR containing the GluN2D subunit. Thus, selective antagonists targeting tPA/GluN2D-containing NMDAR signaling would be of interest to prevent noxious effects of tPA. Results: Here, we compared three putative antagonists of GluN2D-containing NMDAR and we showed that the new compound UBP145 ((2R*,3S*)-1-(9-bromophenan-threne-3-carbonyl)piperazine-2, 3-dicarboxylic acid) is far more selective for GluN2D subunits than memantine and PPDA (phenanthrene derivative (2S*, 3R*)-1-(phenanthrene-2- carbonyl)piperazine-2,3-dicarboxylic acid). Indeed, in vitro, in contrast to the two other compounds, UBP145 prevented NMDA toxicity only in neurons expressing GluN2D (ie, in cortical but not hippocampal neurons). Furthermore, in cultured cortical neurons, UBP145 fully prevented the pro-excitotoxic effect of tPA. In vivo, we showed that UBP145 potently prevented the noxious action of exogenous tPA on excitotoxic damages. Moreover, in a thrombotic stroke model in mice, administration of UBP145 prevented the deleterious effect of late thrombolysis by tPA. Conclusions: In conclusion, tPA exerts noxious effects on neurons by acting on GluN2D-containing NMDAR and pharmacological antagonists of GluN2D-containing NMDAR could be used to prevent the ability of tPA to promote neurotoxicity.

Original languageEnglish (US)
Article number68
JournalMolecular neurodegeneration
Volume6
Issue number1
DOIs
StatePublished - Oct 7 2011

Fingerprint

Tissue Plasminogen Activator
N-Methyl-D-Aspartate Receptors
Neurons
Dicarboxylic Acids
In Vitro Techniques
Memantine
N-Methylaspartate
Neurotransmitter Agents
Central Nervous System
Stroke
Pharmacology

Keywords

  • GluN2D
  • Tissue plasminogen activator
  • UBP145
  • excitotoxicity
  • glutamatergic neurotransmission
  • stroke

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo. / Jullienne, Amandine; Montagne, Axel; Orset, Cyrille; Lesept, Flavie; Jane, David E.; Monaghan, Daniel T.; Maubert, Eric; Vivien, Denis; Ali, Carine.

In: Molecular neurodegeneration, Vol. 6, No. 1, 68, 07.10.2011.

Research output: Contribution to journalArticle

Jullienne, Amandine ; Montagne, Axel ; Orset, Cyrille ; Lesept, Flavie ; Jane, David E. ; Monaghan, Daniel T. ; Maubert, Eric ; Vivien, Denis ; Ali, Carine. / Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo. In: Molecular neurodegeneration. 2011 ; Vol. 6, No. 1.
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abstract = "Background: Tissue plasminogen activator (tPA) exerts multiple functions in the central nervous system, depending on the partner with which it interacts. In particular, tPA acts as a positive neuromodulator of N-methyl-D-aspartate glutamatergic receptors (NMDAR). At the molecular level, it has been proposed that the pro-neurotoxicity mediated by tPA might occur through extrasynaptic NMDAR containing the GluN2D subunit. Thus, selective antagonists targeting tPA/GluN2D-containing NMDAR signaling would be of interest to prevent noxious effects of tPA. Results: Here, we compared three putative antagonists of GluN2D-containing NMDAR and we showed that the new compound UBP145 ((2R*,3S*)-1-(9-bromophenan-threne-3-carbonyl)piperazine-2, 3-dicarboxylic acid) is far more selective for GluN2D subunits than memantine and PPDA (phenanthrene derivative (2S*, 3R*)-1-(phenanthrene-2- carbonyl)piperazine-2,3-dicarboxylic acid). Indeed, in vitro, in contrast to the two other compounds, UBP145 prevented NMDA toxicity only in neurons expressing GluN2D (ie, in cortical but not hippocampal neurons). Furthermore, in cultured cortical neurons, UBP145 fully prevented the pro-excitotoxic effect of tPA. In vivo, we showed that UBP145 potently prevented the noxious action of exogenous tPA on excitotoxic damages. Moreover, in a thrombotic stroke model in mice, administration of UBP145 prevented the deleterious effect of late thrombolysis by tPA. Conclusions: In conclusion, tPA exerts noxious effects on neurons by acting on GluN2D-containing NMDAR and pharmacological antagonists of GluN2D-containing NMDAR could be used to prevent the ability of tPA to promote neurotoxicity.",
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AU - Orset, Cyrille

AU - Lesept, Flavie

AU - Jane, David E.

AU - Monaghan, Daniel T.

AU - Maubert, Eric

AU - Vivien, Denis

AU - Ali, Carine

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