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The Oxygen Free Radicals Originating from Mitochondrial Complex I Contribute to Oxidative Brain Injury Following Hypoxia–Ischemia in Neonatal Mice

2012; Society for Neuroscience; Volume: 32; Issue: 9 Linguagem: Inglês

10.1523/jneurosci.6303-11.2012

1529-2401

Zoya Niatsetskaya, Sergei A. Sosunov, Dzmitry Matsiukevich, Irina Utkina-Sosunova, Veniamin Ratner, Anatoly A. Starkov, Vadim S. Ten,

Cardiac Ischemia and Reperfusion

Oxidative stress and Ca 2+ 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 H 2 O 2 emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to the Ca 2+ -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% O 2 which exacerbated brain injury only in vehicle-treated mice. In vitro , intact brain mitochondria dramatically increased H 2 O 2 emission in response to hyperoxia, resulting in substantial loss of Ca 2+ 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 Ca 2+ 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.