Inhibiting HIF-1 alpha Decreases Expression of TNF-alpha and Caspase-3 in Specific Brain Regions Exposed Kainic Acid-Induced Status Epilepticus

Background/Aims: A recent study demonstrates that pro-inflammatory cytokines (PICs, i.e., IL-1 beta, IL-6 and TNF-alpha) 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 1 alpha (HIF-1 alpha) 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-1 alpha) and etanercept (TNF-alpha receptor antagonist). Methods: ELISA was used to determine the levels of HIF-1 alpha and PICs and western blot analysis was used to examine Caspase-3 expression. Results: Our data show that HIF-1 alpha 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-1 alpha by central infusion of 2-MET significantly decreased the amplified TNF-alpha expression in these brain regions evoked by SE (P<0.05 vs. vehicle control), but did not modify IL-1 beta and IL-6. Our results demonstrate that 2-MET and etanercept attenuated an increase in Caspase-3 evoked by SE. Conclusion: Overall, we suggest that HIF-1 alpha activated by SE is likely to contribute to epileptic activity via a TNF-alpha pathway, which has pharmacological implications to target specific HIF-1 alpha and TNF-alpha pathways for neuronal dysfunction and vulnerability related to epilepsy. (C) 2016 The Author(s) Published by S. Karger AG, Basel