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Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke

Ischemic stroke is the second leading cause of death worldwide. Following an ischemic event, neuronal death is triggered by uncontrolled glutamate release leading to overactivation of glutamate sensitive N-methyl-d-aspartate receptor (NMDAR). For gating, NMDARs require not only the binding of glutam...

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Autores principales: Cappelli, Julia, Khacho, Pamela, Wang, Boyang, Sokolovski, Alexandra, Bakkar, Wafae, Raymond, Sophie, Ahlskog, Nina, Pitney, Julian, Wu, Junzheng, Chudalayandi, Prakash, Wong, Adrian Y.C., Bergeron, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689229/
https://www.ncbi.nlm.nih.gov/pubmed/34977503
http://dx.doi.org/10.1016/j.isci.2021.103539
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author Cappelli, Julia
Khacho, Pamela
Wang, Boyang
Sokolovski, Alexandra
Bakkar, Wafae
Raymond, Sophie
Ahlskog, Nina
Pitney, Julian
Wu, Junzheng
Chudalayandi, Prakash
Wong, Adrian Y.C.
Bergeron, Richard
author_facet Cappelli, Julia
Khacho, Pamela
Wang, Boyang
Sokolovski, Alexandra
Bakkar, Wafae
Raymond, Sophie
Ahlskog, Nina
Pitney, Julian
Wu, Junzheng
Chudalayandi, Prakash
Wong, Adrian Y.C.
Bergeron, Richard
author_sort Cappelli, Julia
collection PubMed
description Ischemic stroke is the second leading cause of death worldwide. Following an ischemic event, neuronal death is triggered by uncontrolled glutamate release leading to overactivation of glutamate sensitive N-methyl-d-aspartate receptor (NMDAR). For gating, NMDARs require not only the binding of glutamate, but also of glycine or a glycine-like compound as a co-agonist. Low glycine doses enhance NMDAR function, whereas high doses trigger glycine-induced NMDAR internalization (GINI) in vitro. Here, we report that following an ischemic event, in vivo, GINI also occurs and provides neuroprotection in the presence of a GlyT1 antagonist (GlyT1-A). Mice pretreated with a GlyT1-A, which increases synaptic glycine levels, exhibited smaller stroke volume, reduced cell death, and minimized behavioral deficits following stroke induction by either photothrombosis or endothelin-1. Moreover, we show evidence that in ischemic conditions, GlyT1-As preserve the vasculature in the peri-infarct area. Therefore, GlyT1 could be a new target for the treatment of ischemic stroke.
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spelling pubmed-86892292021-12-30 Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke Cappelli, Julia Khacho, Pamela Wang, Boyang Sokolovski, Alexandra Bakkar, Wafae Raymond, Sophie Ahlskog, Nina Pitney, Julian Wu, Junzheng Chudalayandi, Prakash Wong, Adrian Y.C. Bergeron, Richard iScience Article Ischemic stroke is the second leading cause of death worldwide. Following an ischemic event, neuronal death is triggered by uncontrolled glutamate release leading to overactivation of glutamate sensitive N-methyl-d-aspartate receptor (NMDAR). For gating, NMDARs require not only the binding of glutamate, but also of glycine or a glycine-like compound as a co-agonist. Low glycine doses enhance NMDAR function, whereas high doses trigger glycine-induced NMDAR internalization (GINI) in vitro. Here, we report that following an ischemic event, in vivo, GINI also occurs and provides neuroprotection in the presence of a GlyT1 antagonist (GlyT1-A). Mice pretreated with a GlyT1-A, which increases synaptic glycine levels, exhibited smaller stroke volume, reduced cell death, and minimized behavioral deficits following stroke induction by either photothrombosis or endothelin-1. Moreover, we show evidence that in ischemic conditions, GlyT1-As preserve the vasculature in the peri-infarct area. Therefore, GlyT1 could be a new target for the treatment of ischemic stroke. Elsevier 2021-12-03 /pmc/articles/PMC8689229/ /pubmed/34977503 http://dx.doi.org/10.1016/j.isci.2021.103539 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Cappelli, Julia
Khacho, Pamela
Wang, Boyang
Sokolovski, Alexandra
Bakkar, Wafae
Raymond, Sophie
Ahlskog, Nina
Pitney, Julian
Wu, Junzheng
Chudalayandi, Prakash
Wong, Adrian Y.C.
Bergeron, Richard
Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke
title Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke
title_full Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke
title_fullStr Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke
title_full_unstemmed Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke
title_short Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke
title_sort glycine-induced nmda receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689229/
https://www.ncbi.nlm.nih.gov/pubmed/34977503
http://dx.doi.org/10.1016/j.isci.2021.103539
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