Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.
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.
Dawson
V L
VL
Neuropharmacology Laboratory, National Institute on Drug Abuse Addiction Research Center, Baltimore, MD 21224.
Dawson
T M
TM
London
E D
ED
Bredt
D S
DS
Snyder
S H
SH
D000818:Animals; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D005333:Fetus; D005971:Glutamates / Q000494:pharmacology*; D006454:Hemoglobins / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D007700:Kinetics; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology
D005971:Glutamates; D006454:Hemoglobins; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D002956:Citrulline; D009569:Nitric Oxide; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D001120:Arginine; D013482:Superoxide Dismutase; D006152:Cyclic GMP