Focal cerebral ischemia and mitochondrial dysfunction in the TNFα-transgenic rat

Jignesh D. Pandya, Patrick G. Sullivan, L. Creed Pettigrew

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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.

Original languageEnglish
Pages (from-to)151-160
Number of pages10
JournalBrain Research
StatePublished - Apr 12 2011

Bibliographical note

Funding Information:
This work was supported by NIH/NINDS grants awarded to the University of Kentucky ( R01s NS048191 [PGS] and NS047375 [LCP]; P30 NS051220 ) and a Merit Review Award from the Medical Research Service, Department of Veterans Affairs (LCP). We thank Susan D. Craddock for her expert technical assistance. Sherry Chandler Williams, ELS, edited the manuscript and prepared the figures.


  • Brain ischemia
  • Calcium homeostasis
  • Mitochondrial bioenergetics
  • Mitochondrial permeability
  • Reactive oxygen species
  • Transgenic rat
  • Tumor necrosis factor alpha
  • transition pore

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology


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