J Neurosci Res. 2007 May 17; [Epub ahead of print] Links
Peroxynitrite-mediated oxidative damage to brain mitochondria:
Protective effects of peroxynitrite scavengers.Singh IN, Sullivan PG,
Hall ED.
Spinal Cord & Brain Injury Research Center, University of Kentucky
College of Medicine, Lexington.
Peroxynitrite-mediated oxidative damage has been implicated in brain
mitochondrial respiratory dysfunction after traumatic brain injury
(TBI), which precedes the onset of neuronal loss. The aim of this
study was to investigate the detrimental effects of the peroxynitrite
donor SIN-1 (3-morpholinosydnonimine) on isolated brain mitochondria
and to screen penicillamine, a stoichiometric (1:1) peroxynitrite-
scavenging agent, and tempol, a catalytic scavenger of peroxynitrite-
derived radicals, as antioxidant mitochondrial protectants. Exposure
of the isolated mitochondria to SIN-1 caused a significant dose-
dependent decrease in the respiratory control ratio and was
accompanied by a significant increase in state II respiration,
followed by significant decreases (P < 0.05) in states III and V.
These functional alterations occurred together with significant
increases in mitochondrial protein carbonyl (PC), lipid peroxidation-
related 4-hydroxynonenal (4-HNE), and 3-nitrotyrosine (3-NT) content.
Penicillamine hydrochloride (10 muM) partially but significantly (P <
0.05) protected against SIN-1-induced decreases in states III and V.
However, a 2.5 muM concentration of tempol was able to significantly
antagonize a 4-fold molar excess (10 muM) concentration of SIN-1 as
effectively as were higher tempol concentrations, consistent with the
likelihood that tempol works by a catalytic mechanism. The protection
of mitochondrial respiration by penicillamine and tempol occurred in
parallel with attenuation of PC, 4-HNE, and 3-NT. These results
indicate that SIN-1 causes mitochondrial oxidative damage and complex
I dysfunction and that antioxidant compounds that target either
peroxynitrite or its radicals may be effective mitochondrial
protectants in the treatment of neural injury. (c) 2007 Wiley-Liss,
Inc.
PMID: 17510982 [PubMed - as supplied by publisher]
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