Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures

Valina L. Dawson, Ted M. Dawson, Edythe D. London, David S. Bredt, Solomon H. Snyder

Research output: Contribution to journalArticlepeer-review

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, Nω-nitro-L-arginine (EC50 = 20 μM) and Nω-monomethyl-L-arginine (EC50 = 170 μM), 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.

Original languageEnglish (US)
Pages (from-to)6368-6371
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Volume88
Issue number14
DOIs
StatePublished - Jul 15 1991

Keywords

  • Endothelium-derived relaxing factor
  • N-methyl-D-aspartate

ASJC Scopus subject areas

  • General

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