title: Focal cerebral ischemia and mitochondrial dysfunction in the TNFα-transgenic rat.
abstract: Post-ischemic neurodegeneration may be accelerated by a cytokine-receptor mediated apoptotic pathway, as shown in a transgenic rat overexpressing tumor necrosis factor-alpha (TNFα) in brain. To further investigate the mechanism of ischemic cellular injury in this animal, we tested the hypothesis that increased synthesis of TNFα augments neuronal death by promoting mitochondrial dysfunction, calcium dysregulation, and oxidative stress. Adult male TNFα-transgenic (TNFα-Tg) and non-transgenic (non-Tg) littermates underwent reversible middle cerebral artery occlusion (MCAO) for 1 hour followed by 1 hour of reperfusion. Cortical mitochondria were isolated from injured (ipsilateral) and uninjured (contralateral) hemispheres of ischemic rats or from pooled hemispheres of control animals. ATP synthesis was attenuated in non-ischemic TNFα-Tg rats, demonstrated by reduction of state III and respiratory control ratio, increased production of reactive oxygen species, and earlier formation of the calcium-induced membrane permeability transition pore. After MCAO, mitochondrial dysfunction was augmented more significantly in ischemic TNFα-Tg brain mitochondria than in non-Tg rats. These results show that mitochondrial dysfunction may be caused by increased brain levels of TNFα without physiological stress but will be exacerbated after MCAO. We conclude that ischemic stress and synthesis of inflammatory cytokines synergistically augment mitochondrial dysfunction to promote neuronal death.
authors.affiliation: Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY, USA.
authors.forename: Jignesh D
authors.initials: JD
authors.lastname: Pandya
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
authors.forename: L Creed
authors.initials: LC
authors.lastname: Pettigrew
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001786:Blood Glucose; D002545:Brain Ischemia / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology / Q000648:ultrastructure; D004579:Electron Transport / Q000235:genetics / Q000502:physiology; D004734:Energy Metabolism / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000235:genetics*; D009243:NAD / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D002118:Calcium