The DOI matches its Crossref record; 75 of the 77 references it cites were found in a registry or an index.
NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo
Open accessAbstract
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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“The hypoxia-inducible transcription factor HIF-1α plays a primary role in the negative regulation of PGC-1α [84].”
From Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis (2021) · cites this paper as [84]
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Cites
Reversible middle cerebral artery occlusion without craniectomy in rats.
Longa, E. Z., Weinstein, P. R., Carlson, S., & Cummins, R. (1989) · Stroke · doi:10.1161/01.str.20.1.84 · Cited by 7,463
Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B., & Seeburg, P. H. (1994) · Neuron · doi:10.1016/0896-6273(94)90210-0 · Cited by 3,535
Benveniste, H., Drejer, J., Schousboe, A., & Diemer, N. H. (1984) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1984.tb05396.x · Cited by 2,863
Bederson, J. B., Pitts, L. H., Tsuji, M., Nishimura, M. C., Davis, R. L., & Bartkowski, H. (1986) · Stroke · doi:10.1161/01.str.17.3.472 · Cited by 2,681
Excitatory Amino Acids as a Final Common Pathway for Neurologic Disorders
Epstein, F. H., Lipton, S. A., & Rosenberg, P. A. (1994) · New England Journal of Medicine · doi:10.1056/nejm199403033300907 · Cited by 2,676
Regulation of neuronal survival by the serine-threonine protein kinase Akt
Dudek, H., Datta, S. R., Franke, T. F., Birnbaum, M. J., Yao, R., Cooper, G. M., Segal, R. A., Kaplan, D. R., & Greenberg, M. E. (1997) · Science · doi:10.1126/science.275.5300.661 · Cited by 2,436
Blockade of NMDA Receptors and Apoptotic Neurodegeneration in the Developing Brain
Ikonomidou, C., Bosch, F., Miksa, M., Bittigau, P., Vöckler, J., Dikranian, K., Tenkova, T. I., Stefovska, V., Turski, L., & Olney, J. W. (1999) · Science · doi:10.1126/science.283.5398.70 · Cited by 2,055
Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P., & Lipton, S. A. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.16.7162 · Cited by 1,958
Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways
Hardingham, G. E., Fukunaga, Y., & Bading, H. (2002) · Nature Neuroscience · doi:10.1038/nn835 · Cited by 1,686
Functional Repression of cAMP Response Element in 6-Hydroxydopamine-treated Neuronal Cells
Chalovich, E. M., Zhu, J.-H., Caltagarone, J., Bowser, R., & Chu, C. T. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602632200 · Cited by 1,385
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NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease
Paoletti, P., Bellone, C., & Zhou, Q. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3504 · Cited by 2,523
Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders
Hardingham, G. E., & Bading, H. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2911 · Cited by 1,644
Functional Repression of cAMP Response Element in 6-Hydroxydopamine-treated Neuronal Cells
Chalovich, E. M., Zhu, J.-H., Caltagarone, J., Bowser, R., & Chu, C. T. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602632200 · Cited by 1,385
Apoptotic Mechanisms After Cerebral Ischemia
Broughton, B. R. S., Reutens, D. C., & Sobey, C. G. (2009) · Stroke · doi:10.1161/strokeaha.108.531632 · Cited by 1,269
Excitotoxicity and stroke: Identifying novel targets for neuroprotection
Lai, T. W., Zhang, S., & Wang, Y. T. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.11.006 · Cited by 1,106
Self-citation
Metadata
- 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
- 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
- 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
- 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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