Mitochondrial protection after traumatic brain injury by scavenging lipid peroxyl radicals.
Mitochondrial dysfunction after traumatic brain injury (TBI) is manifested by increased levels of oxidative damage, loss of respiratory functions and diminished ability to buffer cytosolic calcium. This study investigated the detrimental effects of lipid peroxyl radicals (LOO(*)) and lipid peroxidation (LP) in brain mitochondria after TBI by examining the protective effects of U-83836E, a potent and selective scavenger of LOO(*) radicals. Male CF1 mice were subjected to severe controlled cortical impact TBI (CCI-TBI) and treated with either vehicle or U-83836E initiated i.v. at 15 min post-injury. Calcium (Ca(++)) buffering capacity and respiratory function were measured in isolated cortical mitochondrial samples taken from the ipsilateral hemisphere at 3 and 12 h post-TBI, respectively. In vehicle-treated injured mice, the cortical mitochondrial Ca(++) buffering capacity was reduced by 60% at 3 h post-injury (p < 0.001) and the respiratory control ratio was decreased by 27% at 12 h post-TBI, relative to sham, non-injured mice. U-83836E treatment significantly (p < 0.05) preserved Ca(++) buffering capacity and attenuated the reduction in respiratory control ratio values. Consistent with the functional effects of U-83836E being as a result of an attenuation of mitochondrial oxidative damage, the compound significantly (p < 0.001) reduced LP-generated 4-hydroxynonenal levels in both cortical homogenates and mitochondria at both 3 and 12 h post-TBI. Unexpectedly, U-83836E also reduced peroxynitrite-generated 3-nitrotyrosine in parallel with the reduction in 4-hydroxynonenal. The results demonstrate that LOO(*) radicals contribute to secondary brain mitochondrial dysfunction after TBI by propagating LP and protein nitrative damage in cellular and mitochondrial membranes.
Mustafa
Ayman G
AG
Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA.
Singh
Indrapal N
IN
Wang
Juan
J
Carrico
Kimberly M
KM
Hall
Edward D
ED
D000818:Animals; D001930:Brain Injuries / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D002839:Chromans; D016166:Free Radical Scavengers; D005609:Free Radicals; D018696:Neuroprotective Agents; D010879:Piperazines; C066382:U 78517F; D002118:Calcium
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