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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<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to the Ca<jats:sup>2+<\/jats:sup>-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<jats:sub>2<\/jats:sub>which exacerbated brain injury only in vehicle-treated mice.<jats:italic>In vitro<\/jats:italic>, intact brain mitochondria dramatically increased H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>emission in response to hyperoxia, resulting in substantial loss of Ca<jats:sup>2+<\/jats:sup>buffering capacity. However, in the presence of the C-I inhibitor, rotenone, or the antioxidant, catalase, these effects of hyperoxia were abolished.<\/jats:p><jats:p>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<jats:sup>2+<\/jats:sup>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.<\/jats:p>","DOI":"10.1523\/jneurosci.6303-11.2012","type":"journal-article","created":{"date-parts":[[2012,3,1]],"date-time":"2012-03-01T00:58:28Z","timestamp":1330563508000},"page":"3235-3244","source":"Crossref","is-referenced-by-count":168,"title":["The Oxygen Free Radicals Originating from Mitochondrial Complex I Contribute to Oxidative Brain Injury Following Hypoxia\u2013Ischemia in Neonatal Mice"],"prefix":"10.1523","volume":"32","author":[{"given":"Zoya V.","family":"Niatsetskaya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei A.","family":"Sosunov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dzmitry","family":"Matsiukevich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina V.","family":"Utkina-Sosunova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veniamin I.","family":"Ratner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anatoly A.","family":"Starkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim S.","family":"Ten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2012,2,29]]},"reference":[{"key":"2023041303551365000_32.9.3235.1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4468-06.2007"},{"key":"2023041303551365000_32.9.3235.2","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1046\/j.1471-4159.1995.64052222.x","article-title":"Changes of respiratory chain activity in mitochondrial and synaptosomal fractions isolated from the gerbil brain after graded ischaemia","volume":"64","author":"Allen","year":"1995","journal-title":"J Neurochem"},{"key":"2023041303551365000_32.9.3235.3","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1046\/j.1471-4159.1995.65041698.x","article-title":"Effect of reperfusion following cerebral ischaemia on the activity of the mitochondrial respiratory chain in the gerbil brain","volume":"65","author":"Almeida","year":"1995","journal-title":"J Neurochem"},{"key":"2023041303551365000_32.9.3235.4","doi-asserted-by":"crossref","first-page":"18532","DOI":"10.1016\/S0021-9258(17)46660-9","article-title":"Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow","volume":"268","author":"Ambrosio","year":"1993","journal-title":"J Biol Chem"},{"key":"2023041303551365000_32.9.3235.5","doi-asserted-by":"publisher","DOI":"10.1007\/s10541-005-0102-7"},{"key":"2023041303551365000_32.9.3235.6","doi-asserted-by":"publisher","DOI":"10.1038\/nature03434"},{"key":"2023041303551365000_32.9.3235.7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C500089200"},{"key":"2023041303551365000_32.9.3235.8","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(79)90024-8"},{"key":"2023041303551365000_32.9.3235.9","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1042\/bj1340707","article-title":"The mitochondrial generation of hydrogen peroxide. 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