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 increased H2O2 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. © 2012 the authors.
CITATION STYLE
Z.V., N., S.A., S., D., M., I.V., U.-S., V.I., R., A.A., S., & V.S., T. (2012). The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice. Journal of Neuroscience, 32(9), 3235–3244. Retrieved from http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L364348876 http://www.jneurosci.org/content/32/9/3235.full.pdf+html http://dx.doi.org/10.1523/JNEUROSCI.6303-11.2012
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