title: Inhibiting HIF-1α Decreases Expression of TNF-α and Caspase-3 in Specific Brain Regions Exposed Kainic Acid-Induced Status Epilepticus.
abstract: OBJECTIVE
  A recent study demonstrates that pro-inflammatory cytokines (PICs, i.e., IL-1β, IL-6 and TNF-α) in specific brain regions of rats play a role in regulating kainic acid (KA)-induced status epilepticus (SE) via a GABAergic mechanism. The purposes of this report were to examine contributions of hypoxia inducible factor subtype 1α (HIF-1α) to expression of PICs in these specific brain regions in epileptic rats. Particularly, we investigated the parietal cortex, hippocampus and amygdala. In addition, we further examined expression of Caspase-3 indicating cell apoptosis in those brain regions of epileptic rats after infusing 2-methoxyestradiol (2-MET, inhibitor of HIF-1α) and etanercept (TNF-α receptor antagonist).
  
  
  METHODS
  ELISA was used to determine the levels of HIF-1α and PICs and western blot analysis was used to examine Caspase-3 expression.
  
  
  RESULTS
  Our data show that HIF-1α was significantly increased in the parietal cortex, hippocampus and amygdala 1, 3 and 7 days after induction of SE (P<0.05 vs. control rats). Our results also show that inhibiting HIF-1α by central infusion of 2-MET significantly decreased the amplified TNF-α expression in these brain regions evoked by SE (P<0.05 vs. vehicle control), but did not modify IL-1β and IL-6. Our results demonstrate that 2-MET and etanercept attenuated an increase in Caspase-3 evoked by SE.
  
  
  CONCLUSIONS
  Overall, we suggest that HIF-1α activated by SE is likely to contribute to epileptic activity via a TNF-α pathway, which has pharmacological implications to target specific HIF-1α and TNF-α pathways for neuronal dysfunction and vulnerability related to epilepsy.
authors.affiliation: Department of Neurosurgery, The Fourth Military Medical University Tangdu Hospital, Xi'an, China.
authors.forename: Jixue
authors.initials: J
authors.lastname: Yang
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Weiwen
authors.initials: W
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
mesh_terms: D000077584:2-Methoxyestradiol; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D010296:Parietal Lobe / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D000077584:2-Methoxyestradiol; D053148:Caspase 3; D007608:Kainic Acid