iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite.

iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite. Research Abstract Details 

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iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite. Abstract Text:

Takayuki Kawano,Alexander Kunz,Takato Abe, Girouard,Josef Anrather,Ping Zhou,Costantino Iadecola,

Sublethal injurious stimuli induce tolerance to subsequent lethal insults, a phenomenon termed preconditioning. Inducible nitric oxide synthase (iNOS) is essential for the preconditioning induced by transient bilateral common carotid artery occlusion (BCCAO) or by systemic administration of the endotoxin lipopolysaccharide (LPS). We used a model of brain injury produced by neocortical injection of N-methyl-D-aspartate (NMDA) to investigate the mechanisms by which iNOS-derived nitric oxide (NO) contributes to tolerance induced by LPS or BCCAO. We found that the tolerance is blocked by the iNOS inhibitor aminoguanidine, is not observed in iNOS-null mice, and is rescued by the NO donor DTPA NONOate. Lipopolysaccharide failed to induce preconditioning in mice lacking the nox2 subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, suggesting that superoxide derived from NADPH oxidase is needed for the induction of the tolerance. Because superoxide reacts with NO to form peroxynitrite, we investigated the role of peroxynitrite. We found that LPS induces the peroxynitrite marker 3-nitrotyrosine in cortical neurons and that the peroxynitrite decomposition catalyst FeTPPS abolishes LPS-induced preconditioning. These results suggest that the protective effect of iNOS-derived NO is mediated by peroxynitrite formed by the reaction of NO with NADPH oxidase-derived superoxide. Thus, peroxynitrite, in addition to its well-established deleterious role in ischemic brain injury and neurodegeneration, can also be beneficial by inducing tolerance to excitotoxicity.

iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite. Publishing Authors By Initials

T Kawano,A Kunz,T Abe,H Girouard,J Anrather,P Zhou,C Iadecola,

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iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of cerebral blood flow and metabolism : of

VOLUME: 27

Page Numbers: 1453-62

Journal Abbreviation: J. Cereb. Blood Flow Metab.

ISSN: 0271-678X

DAY: 7

MONTH: 02

YEAR: 2007

iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8112566

iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite. Keywords Mesh Terms:

KEYWORDS: Tyrosine

MESH TERMS: metabolism

Chemical & Substance for Abstract: iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite. Information

Substance Name: NADPH Oxidase

Registry Number: EC 1.6.3.1

Grant and Affiliation Information for iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite.

AFFILIATION: Division of Neurobiology, Weill Medical College of Cornell University, New York, New York 10021, USA.

Country: United States

AGENCY: United States NINDS

GRANT: NS35806

ACRONYM: NS

MEDLINETA: J Cereb Blood Flow Metab

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