TY - JOUR
T1 - Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures
AU - Dawson, Valina L.
AU - Dawson, Ted M.
AU - London, Edythe D.
AU - Bredt, David S.
AU - Snyder, Solomon H.
PY - 1991/7/15
Y1 - 1991/7/15
N2 - 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.
AB - 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.
KW - Endothelium-derived relaxing factor
KW - N-methyl-D-aspartate
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U2 - 10.1073/pnas.88.14.6368
DO - 10.1073/pnas.88.14.6368
M3 - Article
C2 - 1648740
AN - SCOPUS:0025773785
SN - 0027-8424
VL - 88
SP - 6368
EP - 6371
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
ER -