A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds.
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.
Laboratory of Cellular & Molecular Neuroscience, Children's Hospital, Boston, Massachusetts.
S A
SA
Lipton
Y B
YB
Choi
Z H
ZH
Pan
S Z
SZ
Lei
H S
HS
Chen
N J
NJ
Sucher
J
J
Loscalzo
D J
DJ
Singel
J S
JS
Stamler
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D005609:Free Radicals; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D026403:S-Nitrosothiols; D013481:Superoxides / Q000378:metabolism
D005609:Free Radicals; D009566:Nitrates; D016194:Receptors, N-Methyl-D-Aspartate; D026403:S-Nitrosothiols; D013481:Superoxides; D009599:Nitroprusside; C039642:peroxynitric acid; D009569:Nitric Oxide; C002385:linsidomine; C021315:S-nitrosocysteine; D008981:Molsidomine; D005996:Nitroglycerin; D003545:Cysteine