A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds
NaturePublished 1 August 1993
Stuart A. Lipton, Yun‐Beom Choi, Zhuo‐Hua Pan, Sizheng Z. Lei, Huei‐Sheng Vincent Chen, Nikolaus J. Sucher
Citations2,446
SJR quartileQ1
SJR score18.29
SNIP10.16
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
It is reported that NO.-mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O.-2), apparently leading to formation of peroxynitrite (ONOO−), and not by NO.
Abstract
Congeners of nitrogen monoxide (NO) are neuroprotective and neurodestructive. To address this apparent paradox, we considered the effects on neurons of compounds characterized by alternative redox states of NO: nitric oxide (NO.) and nitrosonium ion (NO+). Nitric oxide, generated from NO. donors or synthesized endogenously after NMDA (N-methyl-D-aspartate) receptor activation, can lead to neurotoxicity. Here, we report that NO.- mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O2.-), apparently leading to formation of peroxynitrite (ONOO-), and not by NO. alone. In contrast, the neuroprotective effects of NO result from downregulation of NMDA-receptor activity by reaction with thiol group(s) of the receptor's redox modulatory site. This reaction is not mediated by NO. itself, but occurs under conditions supporting S-nitrosylation of NMDA receptor thiol (reaction or transfer of NO+). Moreover, the redox versatility of NO allows for its interconversion from neuroprotective to neurotoxic species by a change in the ambient redox milieu. The details of this complex redox chemistry of NO may provide a mechanism for harnessing neuroprotective effects and avoiding neurotoxicity in the central nervous system.
Keywords
MedicineBiochemistry, Genetics and Molecular Biology
Proceedings of the National Academy of SciencesApparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide.
7,051 Citations1990Joseph S. Beckman, ThomasJ Beckman +3 more
It is proposed that superoxide dismutase may protect vascular tissue stimulated to produce superoxide and NO under pathological conditions by preventing the formation of peroxynitrite.
NatureLocalization of nitric oxide synthase indicating a neural role for nitric oxide
3,008 Citations1990David S. Bredt, Paul M. Hwang +1 more
It is demonstrated that NO synthase in the brain to be exclusively associated with discrete neuronal populations, and prominent neural localizations provided the first conclusive evidence for a strong association of NO with neurons.
ScienceBiochemistry of Nitric Oxide and Its Redox-Activated Forms
2,742 Citations1992Jonathan S. Stamler, David J. Singel +1 more
The integration of this chemistry with current perspectives of NO biology illuminates many aspects of NO biochemistry, including the enzymatic mechanism of synthesis, the mode of transport and targeting in biological systems, the means by which its toxicity is mitigated, and the function-regulating interaction with target proteins.
Journal of Biological ChemistryPeroxynitrite oxidation of sulfhydryls.
2,485 Citations1991Rafael Radí, Joseph S. Beckman +2 more
Peroxynitrite anion was a less effective thiol-oxidizing agent than its anion, with oxidation presumably mediated by the decomposition products, hydroxyl radical and nitrogen dioxide.
Archives of Biochemistry and BiophysicsPeroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide
2,198 Citations1991Rafael Radí, Joseph S. Beckman +2 more
It is concluded that the conjugate acid of peroxynitrite, peroxlynitrous acid (ONOOH), and/or its decomposition products, i.e., .OH and nitrogen dioxide (.NO2), initiate lipid peroxidation without the requirement of iron.
Proceedings of the National Academy of SciencesNitric oxide mediates glutamate neurotoxicity in primary cortical cultures.
2,185 Citations1991Valina L. Dawson, Ted M. Dawson +3 more
It is established that NO mediates the neurotoxicity of glutamate and Hemoglobin, which complexes NO, prevents neurotoxic effects of both N-methyl-D-aspartate and sodium nitroprusside.
Trends in Pharmacological SciencesExcitatory amino acid neurotoxicity and neurodegenerative disease
1,774 Citations1990Brian S. Meldrum, John Garthwaite
In vivo and in vitro studies of the cytotoxicity of amino acids are reviewed and the contribution of such toxicity to acute and chronic neurodegenerative disorders is summarized.
Archives of Biochemistry and BiophysicsPeroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase
1,493 Citations1992Harry Ischiropoulos, Ling Zhu +5 more
The mechanism appears to involve peroxynitrite initially reacting with the active site copper to form an intermediate with the reactivity of nitronium ion (NO2+), which then nitrates tyrosine on a second molecule of superoxide dismutase.
Proceedings of the National Academy of SciencesS-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds.
1,478 Citations1992Jonathan S. Stamler, Daniel I. Simon +6 more
It is demonstrated that S-nitroso proteins form readily under physiologic conditions and possess EDRF-like effects of vasodilation and platelet inhibition, suggesting that S -nitrosothiol groups in proteins may serve as intermediates in the cellular metabolism of NO and raise the possibility of an additional type of cellular regulatory mechanism.
Chemical Research in ToxicologyPeroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide
1,327 Citations1992Willem H. Koppenol, Juan Moreno +3 more
In theory, activation could involve (1) heterolysis to OH- and NO2+ (delta rxn Gzero' = 13 kcal/mol at pH 7) or (2) homolysis
Annals of NeurologyA novel neuronal messenger molecule in brain: The free radical, nitric oxide
833 Citations1992Ted M. Dawson, Valina L. Dawson +1 more
Nitric oxide in situations of excessive production may function as neurotoxin, suggesting a role for nitricoxide in neurodegenerative disorders, and the catalytic activity of nitric oxide synthase accounts for the NADPH diaphorase staining of neurons that are uniquely resistant ot toxic insults and neurodegenersative disorders.
NeuronEffect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex
749 Citations1992Sizheng Z. Lei, Zhuo-Hua Pan +5 more
The results demonstrate a new pathway for NO regulation of physiological function that is not via cGMP, but instead involves reactions with membrane-bound thiol groups on the NMDA receptor-channel complex.
Biochemical JournalProduction of hydroxyl radicals from the simultaneous generation of superoxide and nitric oxide
701 Citations1992Neil Hogg, Victor Darley‐Usmar +2 more
It is concluded that the simultaneous production of NO and superoxide from SIN-1 results in the formation of hydroxyl radicals.
Proceedings of the National Academy of SciencesAttenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase.
592 Citations1991Hiroyuki Kinouchi, C J Epstein +4 more
Results indicate that increased endogenous SOD activity in brain reduces the level of ischemic damage and support the concept that superoxide radicals play an important role in the pathogenesis of infarction and edema following focal cerebral ischemia.
European Journal of PharmacologyNitric oxide mediates neuronal death after focal cerebral ischemia in the mouse
504 Citations1991Jean-Pierre Nowicki, D. Duval +2 more
HypertensionNitric oxide. A novel signal transduction mechanism for transcellular communication.
499 Citations1990Louis J. Ignarro
The nitric oxide formed diffuses out of its cells of origin and into nearby target cells, where it binds to the heme group of cytosolic guanylate cyclase and thereby causes enzyme activation, which represents a novel and widespread signal transduction mechanism that links extracellular stimuli to the biosynthesis of cyclic GMP in nearbytarget cells.
Journal of Cardiovascular PharmacologyThe Biochemical Pathways of Nitric Oxide Formation from Nitrovasodilators
482 Citations1991Martin Feelisch
Nitrovasodilators are prodrugs of NO and thus principally suited to mimic endogenous NO activities and are increasing interest in using compounds capable of generating NO in situ.
Biochemical PharmacologyNitric oxide generation from nitroprusside by vascular tissue
460 Citations1991James N. Bates, Max T. Baker +2 more
Results show that, apart from photolysis which makes no physiological contribution, release of nitric oxide from nitroprusside, in simple solutions and in biological tissue, occurs after nitroPRusside has undergone reduction and lost cyanide.
Journal of Cardiovascular PharmacologyOn the Mechanism of NO Release from Sydnonimines
313 Citations1989Martin Feelisch, J. Ostrowski +1 more
The Journal of Organic ChemistryOxidation of thiols by nitric oxide and nitrogen dioxide: synthetic utility and toxicological implications
290 Citations1982William A. Pryor, Daniel F. Church +2 more
ScienceL-Cysteine, a Bicarbonate-Sensitive Endogenous Excitotoxin
258 Citations1990John W. Olney, Charles F. Zorumski +2 more
L-cysteine is naturally present in the human brain and in the environment, and is much more powerful than beta-N-methylamino-L-alanine, a bicarbonate-dependent excitotoxin, which has been implicated in an adult neurodegenerative disorder endemic to Guam.
Trends in NeurosciencesModels of neuronal injury in AIDS: another role for the NMDA receptor?
247 Citations1992Stuart A. Lipton
A series of experiments from several different laboratories that offer related hypotheses accounting for neurotoxicity in the brains of AIDS patients are reviewed, finding a final common pathway for neuronal susceptibility appears to be operative, similar to that observed after stroke, trauma and epilepsy.
Proceedings of the National Academy of SciencesExtracellular superoxide dismutase, nitric oxide, and central nervous system O2 toxicity.
241 Citations1992Tim D. Oury, Ye-Shih Ho +2 more
It is suggested that ECSOD increases CNS O2 toxicity by inhibiting O2(-)-mediated inactivation of NO, and the results implicate NO.
Brain ResearchNitric oxide modulates NMDA-induced increases in intracellular Ca2+ in cultured rat forebrain neurons
151 Citations1992Kari R. Hoyt, Liang-Hong Tang +2 more
No-mediated decreases in [Ca2+]i may represent a novel feedback inhibitory mechanism for NO production in the brain, and 8-Bromo-cGMP does not mimic the inhibitory effect of NO suggesting that this effect is not the result of NO stimulation of neuronal cGMP production.
Journal of Neuroscience ResearchRedox modulatory site of the NMDA receptor–channel complex: Regulation by oxidized glutathione
140 Citations1991Nikolaus J. Sucher, Stuart A. Lipton
GSSG displayed little or no effect on [Ca2+]i responses elicited by high extracellular K+ or by kainate, suggesting that, at least under the conditions of the present experiments, GSSG was somewhat selective for the NMDA redox modulatory site.
NeuroreportEffect of NO synthase inhibition on NMDA- and ischaemia-induced hippocampal lesions
128 Citations1992Claudia Moncada, D. Lekieffre +2 more
It is suggested that NO contributes to NMDA toxicity and support data indicating that NMDA receptor antagonists fail to protect against hippocampal CA1 lesions in the 4-vessel occlusion model.
Biochimica et Biophysica Acta (BBA) - BioenergeticsDiscrimination of ascorbate-dependent nonenzymatic and enzymatic, membrane-bound reduction of nitric oxide in denitrifying Pseudomonas perfectomarinus
47 Citations1982Walter G. Zumft, Kurt Frunzke
The marine nitrite-respiring (denitrifying) bacterium, Pseudomonas perfectomarinus, catalyzes by a membrane-bound enzyme the reduction of nitric oxide to nitrous oxide with ascorbic-reduced phenazine methosulfate as electron donor, which could serve as a model to study the formation of the N-N bond in denitrification.
NeuroreportInhibition of nitric oxide synthase protects against hypoxic neuronal injury
45 Citations1992Roi Ann Wallis, Kimberly L. Panizzon +1 more
Results indicate thatNitric oxide generation may mediate acute CA1 neuronal injury during hypoxia, and that inhibition of nitric oxide synthase may be a useful neuroprotective strategy.
Canadian Journal of Physiology and PharmacologyDirect evidence for nitric oxide formation from glyceryl trinitrate during incubation with intact bovine pulmonary artery
44 Citations1992Gerald S. Marks, Brian E. McLaughlin +2 more
Data support the concept that GTN is a nitrovasodilator prodrug acting via the formation of nitric oxide, the first direct chemical measurement ofNitric oxide formation during interaction of GTN with vascular smooth muscle.