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Proc Natl Acad Sci U S A. Jul 15, 1991; 88(14): 6368–6371.

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.

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  • Moncada S, Palmer RM, Higgs EA. Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol. 1989 Jun 1;38(11):1709–1715. [PubMed]
  • Furchgott RF. The 1989 Ulf von Euler lecture. Studies on endothelium-dependent vasodilation and the endothelium-derived relaxing factor. Acta Physiol Scand. 1990 Jun;139(2):257–270. [PubMed]
  • Ignarro LJ. Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol. 1990;30:535–560. [PubMed]
  • Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends Neurosci. 1991 Feb;14(2):60–67. [PubMed]
  • Snyder SH, Bredt DS. Nitric oxide as a neuronal messenger. Trends Pharmacol Sci. 1991 Apr;12(4):125–128. [PubMed]
  • Bult H, Boeckxstaens GE, Pelckmans PA, Jordaens FH, Van Maercke YM, Herman AG. Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature. 1990 May 24;345(6273):346–347. [PubMed]
  • Gillespie JS, Liu XR, Martin W. The effects of L-arginine and NG-monomethyl L-arginine on the response of the rat anococcygeus muscle to NANC nerve stimulation. Br J Pharmacol. 1989 Dec;98(4):1080–1082. [PMC free article] [PubMed]
  • Ramagopal MV, Leighton HJ. Effects of NG-monomethyl-L-arginine on field stimulation-induced decreases in cytosolic Ca2+ levels and relaxation in the rat anococcygeus muscle. Eur J Pharmacol. 1989 Dec 19;174(2-3):297–299. [PubMed]
  • Bredt DS, Snyder SH. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci U S A. 1989 Nov;86(22):9030–9033. [PMC free article] [PubMed]
  • Garthwaite J, Garthwaite G, Palmer RM, Moncada S. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol. 1989 Oct 17;172(4-5):413–416. [PubMed]
  • Bredt DS, Snyder SH. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A. 1990 Jan;87(2):682–685. [PMC free article] [PubMed]
  • Hibbs JB, Jr, Vavrin Z, Taintor RR. L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J Immunol. 1987 Jan 15;138(2):550–565. [PubMed]
  • Bredt DS, Hwang PM, Snyder SH. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature. 1990 Oct 25;347(6295):768–770. [PubMed]
  • Choi DW. Cerebral hypoxia: some new approaches and unanswered questions. J Neurosci. 1990 Aug;10(8):2493–2501. [PubMed]
  • Meldrum B, Garthwaite J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci. 1990 Sep;11(9):379–387. [PubMed]
  • Koh JY, Choi DW. Vulnerability of cultured cortical neurons to damage by excitotoxins: differential susceptibility of neurons containing NADPH-diaphorase. J Neurosci. 1988 Jun;8(6):2153–2163. [PubMed]
  • Javitt DC, Zukin SR. Interaction of [3H]MK-801 with multiple states of the N-methyl-D-aspartate receptor complex of rat brain. Proc Natl Acad Sci U S A. 1989 Jan;86(2):740–744. [PMC free article] [PubMed]
  • Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. [PubMed]
  • Hecker M, Mitchell JA, Harris HJ, Katsura M, Thiemermann C, Vane JR. Endothelial cells metabolize NG-monomethyl-L-arginine to L-citrulline and subsequently to L-arginine. Biochem Biophys Res Commun. 1990 Mar 30;167(3):1037–1043. [PubMed]
  • Dwyer MA, Bredt DS, Snyder SH. Nitric oxide synthase: irreversible inhibition by L-NG-nitroarginine in brain in vitro and in vivo. Biochem Biophys Res Commun. 1991 May 15;176(3):1136–1141. [PubMed]
  • Stuehr DJ, Nathan CF. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. [PMC free article] [PubMed]
  • Sessa WC, Hecker M, Mitchell JA, Vane JR. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: L-glutamine inhibits the generation of L-arginine by cultured endothelial cells. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8607–8611. [PMC free article] [PubMed]
  • Koh JY, Goldberg MP, Hartley DM, Choi DW. Non-NMDA receptor-mediated neurotoxicity in cortical culture. J Neurosci. 1990 Feb;10(2):693–705. [PubMed]
  • Knowles RG, Palacios M, Palmer RM, Moncada S. Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5159–5162. [PMC free article] [PubMed]
  • Marletta MA. Nitric oxide: biosynthesis and biological significance. Trends Biochem Sci. 1989 Dec;14(12):488–492. [PubMed]
  • Ferrante RJ, Kowall NW, Beal MF, Richardson EP, Jr, Bird ED, Martin JB. Selective sparing of a class of striatal neurons in Huntington's disease. Science. 1985 Nov 1;230(4725):561–563. [PubMed]
  • Kowall NW, Beal MF. Cortical somatostatin, neuropeptide Y, and NADPH diaphorase neurons: normal anatomy and alterations in Alzheimer's disease. Ann Neurol. 1988 Feb;23(2):105–114. [PubMed]
  • Uemura Y, Kowall NW, Beal MF. Selective sparing of NADPH-diaphorase-somatostatin-neuropeptide Y neurons in ischemic gerbil striatum. Ann Neurol. 1990 Jun;27(6):620–625. [PubMed]
  • Koh JY, Peters S, Choi DW. Neurons containing NADPH-diaphorase are selectively resistant to quinolinate toxicity. Science. 1986 Oct 3;234(4772):73–76. [PubMed]
  • Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1620–1624. [PMC free article] [PubMed]
  • Hibbs JB, Jr, Taintor RR, Vavrin Z, Rachlin EM. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988 Nov 30;157(1):87–94. [PubMed]
  • Murphy TH, De Long MJ, Coyle JT. Enhanced NAD(P)H:quinone reductase activity prevents glutamate toxicity produced by oxidative stress. J Neurochem. 1991 Mar;56(3):990–995. [PubMed]

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