Cited by 2,174Neuroscience and Neuropharmacology ResearchNitric Oxide and Endothelin EffectsAmino Acid Enzymes and Metabolism

Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.

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Dawson, V L, Dawson, T M, London, E D, Bredt, D S, Snyder, S H·1991·Proceedings of the National Academy of Sciences

Abstract

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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Crossref · 10.1073/pnas.88.14.6368

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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
Published
1991-07-15
Volume
88
Issue
14
Pages
6368-6371
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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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