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A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds

Abstract

CONGENERS of nitrogen monoxide (NO) are neuroprotective and neurodestructive1– 7. 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+)8. Nitric oxide, generated from NO. donors or synthesized endogenously after NMDA (N-methyl-D-aspartate) receptor activation, can lead to neurotoxicity3,4. Here, we report 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. 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 site1. 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.

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Lipton, S., Choi, YB., Pan, ZH. et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626–632 (1993). https://doi.org/10.1038/364626a0

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