Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation
Open accessAbstract
Using the fluorescent dye 2′,7′-dichlorodihydrofluorescein (DCF-H2) we investigated the role of glutamate in the production of reactive oxygen species (ROS) in cultured neurons from fetal rat forebrain. The addition of an excitotoxic concentration of glutamate (100 microM) produced a generalized decrease in cellular DCF fluorescence accompanied by local areas of increased fluorescence around the margins of the cell body that could be observed within 2–4 min of glutamate exposure. Increases in fluorescence were dependent on NMDA receptor activation and Ca2+ entry and were blocked by the mitochondrial proton ionophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP). Additional studies suggested that the generalized decrease in fluorescence was due to intracellular acidification. These studies suggest a critical role for mitochondria in the production of ROS in association with glutamate excitotoxicity, and additionally demonstrate the feasibility of measuring the production of ROS at the level of the single cell.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Toxic levels of glutamate induce morphological changes in neurons, manifesting in deformed dendrites and expanded rounded neurons.
“These toxic levels of glutamate induce morphological changes in neurons, manifesting in deformed dendrites and expanded rounded neurons (Reynolds’ and Hastings, 1995; Jellinger, 1999; Adamchik et al., 2000; Robert et al., 2002; Youdim et al., 2002; García et al., 2005), showing degenerative cell (Kang et al., 2020; Erkartal et al., 2025) and neuronal death (Weidinger et al., 2023).”
From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Reynolds’ and Hastings, 1995
The Results (page not available in our copy) note some neuronal swelling after glutamate addition, supporting a change in cell shape. They do not describe deformed dendrites or expanded, rounded neurons. The small round cells mentioned elsewhere in the Results did not respond to glutamate. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Probing Mitochondria in Living Cells with Rhodamine 123
Chen, L. B., Summerhayes, I. C., Johnson, L. V., Walsh, M. L., Bernal, S. D., & Lampidis, T. J. (1982) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.1982.046.01.018 · Cited by 184 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Rajdev S, Reynolds IJ (1994) Glutamate-induced intracellular calcium changes and neurotoxicity in vitro: effects of chemical ischemia. Neuroscience, in press.
- White RJ, Reynolds IJ (1995) Mitochondria and Na+/Ca2+ exchange buffer glutamate-induced calcium loads in cultured cortical neurons. J Neurosci, in press.
Cited by
Sorted by citations
Lemasters, J. J., Nieminen, A.-L., Qian, T., Trost, L. C., Elmore, S. P., Nishimura, Y., Crowe, R. A., Cascio, W. E., Bradham, C. A., Brenner, D. A., et al. (1998) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(98)00112-1 · Cited by 1,387 · see citing works
13 reasons why the brain is susceptible to oxidative stress
Cobley, J. N., Fiorello, M. L., & Bailey, D. M. (2018) · Redox Biology · doi:10.1016/j.redox.2018.01.008 · Cited by 1,215 · see citing works
Flavonoids Protect Neuronal Cells from Oxidative Stress by Three Distinct Mechanisms
Ishige, K., Schubert, D., & Sagara, Y. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00498-6 · Cited by 841 · see citing works
Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity
Ioannou, M. S., Jackson, J., Sheu, S.-H., Chang, C.-L., Weigel, A. V., Liu, H., Pasolli, H. A., Xu, C. S., Pang, S., Matthies, D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.04.001 · Cited by 760 · see citing works
Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory
Massaad, C. A., & Klann, E. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3208 · Cited by 635 · see citing works
Votyakova, T. V., & Reynolds, I. J. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00548.x · Cited by 601 · see citing works
Self-citationExcitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration
Verma, M., Lizama, B. N., & Chu, C. T. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-021-00278-7 · Cited by 451 · see citing works
Adam-Vizi, V. (2005) · Antioxidants & Redox Signaling · doi:10.1089/ars.2005.7.1140 · Cited by 439 · see citing works
Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress
Tretter, L., & Adam-Vizi, V. (2005) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2005.1764 · Cited by 434 · see citing works
Shih, A. Y., Li, P., & Murphy, T. H. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4014-05.2005 · Cited by 413 · see citing works
Huntington's disease: from pathology and genetics to potential therapies
Imarisio, S., Carmichael, J., Korolchuk, V., Chen, C.-W., Saiki, S., Rose, C., Krishna, G., Davies, J. E., Ttofi, E., Underwood, B. R., et al. (2008) · Biochemical Journal · doi:10.1042/bj20071619 · Cited by 409 · see citing works
Sensi, S. L., Yin, H. Z., Carriedo, S. G., Rao, S. S., & Weiss, J. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.5.2414 · Cited by 408 · see citing works
Beckhauser, T. F., Francis-Oliveira, J., & De Pasquale, R. (2016) · Journal of Experimental Neuroscience · doi:10.4137/jen.s39887 · Cited by 301 · see citing works
Shih, A. Y., Imbeault, S., Barakauskas, V., Erb, H., Jiang, L., Li, P., & Murphy, T. H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414635200 · Cited by 273 · see citing works
Calkins, M. J., Jakel, R. J., Johnson, D. A., Chan, K., Kan, Y. W., & Johnson, J. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408487101 · Cited by 247 · see citing works
Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation
Liu, G., Yu, J., Ding, J., Xie, C., Sun, L., Rudenko, I., Zheng, W., Sastry, N., Luo, J., Rudow, G., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72176 · Cited by 166 · see citing works
Satoh, T., Sakai, N., Enokido, Y., Uchiyama, Y., & Hatanaka, H. (1996) · Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a021447 · Cited by 146 · see citing works
Tsatmali, M., Walcott, E. C., & Crossin, K. L. (2005) · Brain Research · doi:10.1016/j.brainres.2005.01.087 · Cited by 133 · see citing works
Kumar, P., & Kumar, A. (2009) · Journal of Medicinal Food · doi:10.1089/jmf.2008.0028 · Cited by 120 · see citing works
Prakash, P., Manchanda, P., Paouri, E., Bisht, K., Sharma, K., Rajpoot, J., Wendt, V., Hossain, A., Wijewardhane, P. R., Randolph, C. E., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.029 · Cited by 104 · see citing works
Parihar, M. S., & Hemnani, T. (2003) · Journal of Biosciences · doi:10.1007/bf02970142 · Cited by 102 · see citing works
MFN2 couples glutamate excitotoxicity and mitochondrial dysfunction in motor neurons
Wang, W., Zhang, F., Li, L., Tang, F., Siedlak, S. L., Fujioka, H., Liu, Y., Su, B., Pi, Y., & Wang, X. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.617167 · Cited by 103 · see citing works
Slyepchenko, A., Maes, M., Köhler, C. A., Anderson, G., Quevedo, J., Alves, G. S., Berk, M., Fernandes, B. S., & Carvalho, A. F. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.02.002 · Cited by 89 · see citing works
A role for reactive oxygen/nitrogen species and iron on neuronal synaptic plasticity
Hidalgo, C., Carrasco, M. A., Muñoz, P., & Núñez, M. T. (2007) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.9.245 · Cited by 81 · see citing works
Wang, X., Pinto-Duarte, A., Sejnowski, T. J., & Behrens, M. M. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4907 · Cited by 46 · see citing works
The role of suboptimal mitochondrial function in vulnerability to post‐traumatic stress disorder
Preston, G., Kirdar, F., & Kozicz, T. (2018) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-018-0168-1 · Cited by 36 · see citing works
Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions
Choi, H. K., Chen, M., Goldston, L. L., & Lee, K.-B. (2024) · Nano Convergence · doi:10.1186/s40580-024-00426-5 · Cited by 26 · see citing works
Slyepchenko, A., Brunoni, A. R., McIntyre, R. S., Quevedo, J., & Carvalho, A. F. (2016) · Current Molecular Medicine · doi:10.2174/1566524016666160126144601 · Cited by 14 · see citing works
Vaglio-Garro, A., Theuermann, M., Sweis, K. E., Zavadskis, S., Kokas, M., Környei, Z., Karas, M., Tretter, L., Komlódi, T., Weidinger, A., et al. (2026) · eneuro · doi:10.1523/eneuro.0439-25.2026
- Authors
- Reynolds, I., & Hastings, T.
- Affiliations
- University of Pittsburgh (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1995-05-01
- Volume
- 15
- Issue
- 5
- Pages
- 3318-3327
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6578215
- OpenAlex
- W1909841186
- Cited by
- 777
- References
- 1
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 13 · 2023: 11 · 2022: 15 · 2021: 28 · 2020: 19 · 2019: 16 · 2018: 17 · 2017: 16 · 2016: 20 · 2015: 15 · 2014: 33 · 2013: 24 · 2012: 24
- FWCI
- 14.53
- 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
- American Heart Association
- National Institutes of Health (1f32ns009076-01)
- U.S. Public Health Service
- National Institute of Neurological Disorders and Stroke (NS 19608, NS09076)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- glutamate excitotoxicity, reactive oxygen species, NMDA receptor activation, forebrain neurons, mitochondrial ROS production, intracellular acidification, calcium influx, FCCP
- MeSH terms
- Animals, Arginine, Calcium, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, Cells, Cultured, Cerebral Cortex, Fetus, Indomethacin, Kainic Acid, Kinetics, Neurons, Masoprocol, Spectrometry, Fluorescence, Time Factors, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Dizocilpine Maleate, Prosencephalon, Rats, Sprague-Dawley, Reactive Oxygen Species, Receptors, Glutamate, Excitatory Amino Acid Antagonists, Glutamic Acid, 6-Cyano-7-nitroquinoxaline-2,3-dione, Nitroarginine, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
