Cited by 777Neuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration MechanismsAcute Ischemic Stroke Management

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NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo

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Liu, Yitao, Wong, Tak Pan, Aarts, Michelle, Rooyakkers, Amanda, Liu, Lidong, Lai, Ted Weita, Wu, Dong Chuan, Lu, Jie, Tymianski, Michael, Craig, Ann Marie, Wang, Yu Tian·2007·The Journal of Neuroscience

DOI 10.1523/jneurosci.0116-07.2007PMC PMC6672582

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Abstract

Well-documented experimental evidence from both in vitro and in vivo models of stroke strongly supports the critical involvement of NMDA receptor-mediated excitotoxicity in neuronal damage after stroke. Despite this, the results of clinical trials testing NMDA receptor antagonists as neuroprotectants after stroke and brain trauma have been discouraging. Here, we report that in mature cortical cultures, activation of either synaptic or extrasynaptic NR2B-containing NMDA receptors results in excitotoxicity, increasing neuronal apoptosis. In contrast, activation of either synaptic or extrasynaptic NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action against both NMDA receptor-mediated and non-NMDA receptor-mediated neuronal damage. A similar opposing action of NR2B and NR2A in mediating cell death and cell survival was also observed in an in vivo rat model of focal ischemic stroke. Moreover, we found that blocking NR2B-mediated cell death was effective in reducing infarct volume only when the receptor antagonist was given before the onset of stroke and not 4.5 h after stroke. In great contrast, activation of NR2A-mediated cell survival signaling with administration of either glycine alone or in the presence of NR2B antagonist significantly attenuated ischemic brain damage even when delivered 4.5 h after stroke onset. Together, the present work provides a molecular basis for the dual roles of NMDA receptors in promoting neuronal survival and mediating neuronal damage and suggests that selective enhancement of NR2A-containing NMDA receptor activation with glycine may constitute a promising therapy for stroke.

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Additional file 13 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
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Additional file 8 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
Lim, J. R., Lee, H. J., Jung, Y. H., Kim, J. S., Chae, C. W., Kim, S. Y., & Han, H. J. (2020) · Figshare · doi:10.6084/m9.figshare.12799428
Additional file 1 of Proteome profiling of different rat brain regions reveals the modulatory effect of prolonged maternal separation on proteins involved in cell death-related processes
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Additional file 11 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
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Additional file 6 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
Lim, J. R., Lee, H. J., Jung, Y. H., Kim, J. S., Chae, C. W., Kim, S. Y., & Han, H. J. (2020) · Figshare · doi:10.6084/m9.figshare.12799422
Additional file 4 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
Lim, J. R., Lee, H. J., Jung, Y. H., Kim, J. S., Chae, C. W., Kim, S. Y., & Han, H. J. (2020) · Figshare · doi:10.6084/m9.figshare.12799416
Additional file 8 of Proteome profiling of different rat brain regions reveals the modulatory effect of prolonged maternal separation on proteins involved in cell death-related processes
Drastichová, Z., Rudajev, V., Pallag, G., & Novotny, J. (2021) · Figshare · doi:10.6084/m9.figshare.13788318
Additional file 10 of Proteome profiling of different rat brain regions reveals the modulatory effect of prolonged maternal separation on proteins involved in cell death-related processes
Drastichová, Z., Rudajev, V., Pallag, G., & Novotny, J. (2021) · Figshare · doi:10.6084/m9.figshare.13788291
Additional file 1 of Galantamine prevents and reverses neuroimmune induction and loss of adult hippocampal neurogenesis following adolescent alcohol exposure
Macht, V. A., Vetreno, R. P., Elchert, N., & Crews, F. T. (2021) · Figshare · doi:10.6084/m9.figshare.16633403
Additional file 7 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
Lim, J. R., Lee, H. J., Jung, Y. H., Kim, J. S., Chae, C. W., Kim, S. Y., & Han, H. J. (2020) · Figshare · doi:10.6084/m9.figshare.12799425
Additional file 9 of Proteome profiling of different rat brain regions reveals the modulatory effect of prolonged maternal separation on proteins involved in cell death-related processes
Drastichová, Z., Rudajev, V., Pallag, G., & Novotny, J. (2021) · Figshare · doi:10.6084/m9.figshare.13788321
Additional file 10 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
Lim, J. R., Lee, H. J., Jung, Y. H., Kim, J. S., Chae, C. W., Kim, S. Y., & Han, H. J. (2020) · Figshare · doi:10.6084/m9.figshare.12799398
Additional file 9 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
Lim, J. R., Lee, H. J., Jung, Y. H., Kim, J. S., Chae, C. W., Kim, S. Y., & Han, H. J. (2020) · Figshare · doi:10.6084/m9.figshare.12799431
Additional file 5 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
Lim, J. R., Lee, H. J., Jung, Y. H., Kim, J. S., Chae, C. W., Kim, S. Y., & Han, H. J. (2020) · Figshare · doi:10.6084/m9.figshare.12799419
Additional file 3 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
Lim, J. R., Lee, H. J., Jung, Y. H., Kim, J. S., Chae, C. W., Kim, S. Y., & Han, H. J. (2020) · Figshare · doi:10.6084/m9.figshare.12799413
Additional file 3 of Proteome profiling of different rat brain regions reveals the modulatory effect of prolonged maternal separation on proteins involved in cell death-related processes
Drastichová, Z., Rudajev, V., Pallag, G., & Novotny, J. (2021) · Figshare · doi:10.6084/m9.figshare.13788303
Additional file 2 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
Lim, J. R., Lee, H. J., Jung, Y. H., Kim, J. S., Chae, C. W., Kim, S. Y., & Han, H. J. (2020) · Figshare · doi:10.6084/m9.figshare.12799410
Additional file 12 of Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation
Lim, J. R., Lee, H. J., Jung, Y. H., Kim, J. S., Chae, C. W., Kim, S. Y., & Han, H. J. (2020) · Figshare · doi:10.6084/m9.figshare.12799404
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Authors: Liu, Y., Wong, T. P., Aarts, M., Rooyakkers, A., Liu, L., Lai, T. W., Wu, D. C., Lu, J., Tymianski, M., Craig, A. M., & Wang, Y. T.
Affiliations: University of British Columbia (CA)
Toronto Western Hospital (CA)
University of British Columbia Hospital (CA)
Corresponding author: Wang, Yu Tian
ORCID: Liu, Yitao
Wong, Tak Pan
Aarts, Michelle
Liu, Lidong
Lai, Ted Weita
Wu, Dong Chuan
Lu, Jie
Tymianski, Michael
Craig, Ann Marie
Wang, Yu Tian
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2007-03-14
Volume: 27
Issue: 11
Pages: 2846-2857
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.0116-07.2007
PMC: PMC6672582
OpenAlex: W2097095684
Cited by: 773
References: 77
Citations by year: 2026: 10 · 2025: 25 · 2024: 22 · 2023: 30 · 2022: 23 · 2021: 51 · 2020: 43 · 2019: 35 · 2018: 44 · 2017: 39 · 2016: 50 · 2015: 39 · 2014: 58 · 2013: 48 · 2012: 72
FWCI: 18.71
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 184 d)
Locations: Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Heart and Stroke Foundation of Canada
Heart and Stroke Foundation of British Columbia and Yukon
Canadian Stroke Network
Michael Smith Health Research BC
Novartis Pharma
Canadian Institutes of Health Research
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
Keywords: NMDA receptor subunits, NR2A, NR2B, excitotoxicity, ischemic stroke, neuronal apoptosis, neuroprotection, glycine, extrasynaptic NMDA receptors, synaptic NMDA receptors, infarct size, cortical cultures, focal cerebral ischemia, NMDA receptor antagonists
MeSH terms: Animals, Cells, Cultured, Brain Ischemia, Male, Mice, Transgenic, Neurons, Receptors, N-Methyl-D-Aspartate, Cell Death, Rats, Sprague-Dawley, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Protein Subunits, Mice, Rats

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NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo

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