Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.
Open accessAbstract
Nitric oxide (NO) mediates several biological actions, including relaxation of blood vessels, cytotoxicity of activated macrophages, and formation of cGMP by activation of glutamate receptors in cerebellar slices. Nitric oxide synthase (EC 1.14.23.-) immunoreactivity is colocalized with nicotinamide adenine di-nucleotide phosphate diaphorase in neurons that are uniquely resistant to toxic insults. We show that the nitric oxide synthase inhibitors, N omega-nitro-L-arginine (EC50 = 20 microM) and N omega-monomethyl-L-arginine (EC50 = 170 microM), prevent neurotoxicity elicited by N-methyl-D-aspartate and related excitatory amino acids. This effect is competitively reversed by L-arginine. Depletion of the culture medium of arginine by arginase or arginine-free growth medium completely attenuates N-methyl-D-aspartate toxicity. Sodium nitroprusside, which spontaneously releases NO, produces dose-dependent cell death that parallels cGMP formation. Hemoglobin, which complexes NO, prevents neurotoxic effects of both N-methyl-D-aspartate and sodium nitroprusside. These data establish that NO mediates the neurotoxicity of glutamate.
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- Authors
- Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S., & Snyder, S. H.
- Affiliations
- National Institute on Drug Abuse (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1991-07-15
- Volume
- 88
- Issue
- 14
- Pages
- 6368-6371
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC52084
- OpenAlex
- W1988726352
- Cited by
- 2,174
- References
- 34
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 13 · 2023: 12 · 2022: 11 · 2021: 16 · 2020: 22 · 2019: 14 · 2018: 14 · 2017: 27 · 2016: 27 · 2015: 37 · 2014: 37 · 2013: 29 · 2012: 44
- FWCI
- 45.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dana Foundation
- Pfizer
- American Academy of Neurology
- U.S. Public Health Service (DA-00266, DA-00074, GM-07309)
- National Institute on Drug Abuse (DA 00074, DA271-90-7408, DA.00266)
- National Institute of General Medical Sciences
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- nitric oxide, glutamate excitotoxicity, nitric oxide synthase, N-methyl-D-aspartate, excitatory amino acids, L-NNA, L-arginine, arginase, sodium nitroprusside, cyclic GMP, hemoglobin, cortical neurons, excitotoxicity
- MeSH terms
- Animals, Arginine, Cell Survival, Cells, Cultured, Citrulline, Fetus, Glutamates, Cyclic GMP, Hemoglobins, Hippocampus, Kinetics, Neurons, Neurotoxins, Nitric Oxide, Superoxide Dismutase, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Dizocilpine Maleate, Rats
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