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

Nature. 1993 Aug 12;364(6438):626-32. doi: 10.1038/364626a0.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Cell Death / drug effects
  • Cells, Cultured
  • Cysteine / analogs & derivatives
  • Cysteine / pharmacology
  • Free Radicals
  • Molsidomine / analogs & derivatives
  • Molsidomine / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nitrates / metabolism
  • Nitric Oxide / metabolism*
  • Nitroglycerin / pharmacology
  • Nitroprusside / pharmacology
  • Oxidation-Reduction
  • Rats
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • S-Nitrosothiols*
  • Superoxides / metabolism


  • Free Radicals
  • Nitrates
  • Receptors, N-Methyl-D-Aspartate
  • S-Nitrosothiols
  • Superoxides
  • Nitroprusside
  • peroxynitric acid
  • Nitric Oxide
  • linsidomine
  • S-nitrosocysteine
  • Molsidomine
  • Nitroglycerin
  • Cysteine