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- Title
The Oxygen Free Radicals Originating from Mitochondrial Complex I Contribute to Oxidative Brain Injury Following Hypoxia-Ischemia in Neonatal Mice.
- Authors
Niatsetskaya, Zoya V.; Sosunov, Sergei A.; Matsiukevich, Dzmitry; Utkina-Sosunova, Irina V.; Ratner, Veniamin I.; Starkov, Anatoly A.; Ten, Vadim S.
- Abstract
Oxidative stress and Ca2+ toxicity are mechanisms of hypoxic-ischemic (HI) brain injury. This work investigates if partial inhibition of mitochondrial respiratory chain protects HI brain by limiting a generation of oxidative radicals during reperfusion. HI insult was produced in p10 mice treated with complex I (C-I) inhibitor, pyridaben, or vehicle. Administration of P significantly decreased the extent of HI injury. Mitochondria isolated from the ischemic hemisphere in pyridaben-treated animals showed reduced H2O2 emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to the Ca2+-triggered opening of the permeability transition pore. A protective effect of pyridaben administration was also observed when the reperfusion-driven oxidative stress was augmented by the exposure to 100% O2 which exacerbated brain injury only in vehicle-treated mice. In vitro, intact brain mitochondria dramatically increasedH2O2 emission in response to hyperoxia, resulting in substantial loss of Ca2+buffering capacity. However, in the presence of the C-I inhibitor, rotenone, or the antioxidant, catalase, these effects of hyperoxia were abolished. Our data suggest that the reperfusion-driven recovery of C-I-dependent mitochondrial respiration contributes not only to the cellular survival, but also causes oxidative damage to the mitochondria, potentiating a loss of Ca2+ buffering capacity. This highlights a novel neuroprotective strategy against HI brain injury where the major therapeutic principle is a pharmacological attenuation, rather than an enhancement of mitochondrial oxidative metabolism during early reperfusion
- Subjects
REACTIVE oxygen species; MITOCHONDRIAL membranes; OXIDATIVE stress; BRAIN injuries; HYPOXEMIA; ISCHEMIA; LABORATORY mice; PYRIDABEN; ENZYME inhibitors
- Publication
Journal of Neuroscience, 2012, Vol 32, Issue 9, p3235
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.6303-11.2012