The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice Academic Article uri icon


MeSH Major

  • Brain Injuries
  • Electron Transport Complex I
  • Free Radicals
  • Hypoxia-Ischemia, Brain
  • Mitochondria
  • Oxidative Stress
  • Oxygen


  • 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.

publication date

  • February 29, 2012



  • Academic Article



  • eng

PubMed Central ID

  • PMC3296485

Digital Object Identifier (DOI)

  • 10.1523/JNEUROSCI.6303-11.2012

PubMed ID

  • 22378894

Additional Document Info

start page

  • 3235

end page

  • 44


  • 32


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