Abstract
BackgroundTissue 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.ResultsHere, 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.ConclusionsIn 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.
Highlights
Tissue plasminogen activator exerts multiple functions in the central nervous system, depending on the partner with which it interacts
UBP145 selectively prevents Tissue plasminogen activator (tPA)-promoted neurotoxicity mediated by GluN2D-containing NMDA receptor In a paradigm of rapidly triggered excitotoxicity, we have previously shown that tPA potentiates neuronal death of cortical neurons but not of hippocampal neurons
This differential sensitivity of cortical versus hippocampal neurons was respectively attributed to the presence and absence of GluN2D subunits in N-methylD-aspartate glutamatergic receptors (NMDAR) at both the mRNA and protein levels [23]
Summary
Tissue plasminogen activator (tPA) exerts multiple functions in the central nervous system, depending on the partner with which it interacts. It has been proposed that the proneurotoxicity mediated by tPA might occur through extrasynaptic NMDAR containing the GluN2D subunit. Tissue plasminogen activator (tPA) is a serine protease initially described to promote vascular fibrinolysis by converting plasminogen into active plasmin [1]. TPA is not just a vascular protease, since it is expressed by nerve cells and exerts important functions in the. The pleiotropic functions of tPA in the central nervous system can be explained by several mechanisms. There is strong evidence that the direct or indirect interaction of tPA with the N-methyl-D-aspartate receptor (NMDAR) exerts a positive neuromodulatory action [10,14,15]. NMDARs differentially control neuronal outcome (trophism versus neurotoxicity) depending on their neuronal localization (synaptic and extrasynaptic) [19,20], their subunit composition [21] and/or their anchorage with cytoplasmic or membrane-associated proteins [22]
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