دورية أكاديمية
Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo
| العنوان: | Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo |
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| المؤلفون: | Maubert Eric, Monaghan Daniel T, Jane David E, Lesept Flavie, Orset Cyrille, Montagne Axel, Jullienne Amandine, Vivien Denis, Ali Carine |
| المصدر: | Molecular Neurodegeneration, Vol 6, Iss 1, p 68 (2011) |
| بيانات النشر: | BMC |
| سنة النشر: | 2011 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Tissue plasminogen activator, GluN2D, UBP145, excitotoxicity, stroke, glutamatergic neurotransmission, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1750-1326 |
| العلاقة: | http://www.molecularneurodegeneration.com/content/6/1/68Test; https://doaj.org/toc/1750-1326Test; https://doaj.org/article/799635682fa248c8b8cc669c3f51fa7cTest |
| DOI: | 10.1186/1750-1326-6-68 |
| الإتاحة: | https://doi.org/10.1186/1750-1326-6-68Test https://doaj.org/article/799635682fa248c8b8cc669c3f51fa7cTest |
| رقم الانضمام: | edsbas.512133D3 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 17501326 |
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| DOI: | 10.1186/1750-1326-6-68 |