Nuclear factor-κB regulates seizure threshold and gene transcription following convulsant stimulation

We evaluated a role for the nuclear factor-kappa B (NF-kappa B) pathway in the regulation of seizure susceptibility and transcriptional activation during prolonged, continuous seizures (status epilepticus). Using two functionally distinct NF-kappa B inhibitors we observed a decrease in latency to onset of kainate-induced seizures and status epilepticus. To assess NF-kappa B transcriptional activation, we evaluated inhibitor kappa B alpha (I kappa B alpha) and brain-derived neurotrophic factor (bdnf) gene targets. Inhibition of the NF-kappa B signaling pathway significantly attenuated the increases in I kappa B alpha and bdnf mRNA levels that occurred during prolonged seizure activity, suggesting that the NF-kappa B pathway was involved in the up-regulation of these transcripts during status epilepticus. DNA-binding studies and chromatin immunoprecipitation assays using hippocampal extracts from animals with status epilepticus revealed that NF-kappa B subunits were associated with the candidate kappa B-binding elements within promoter 1 of the bdnf gene. The pattern of association was different for the p50 and p65 subunits supporting complex NF-kappa B modifications within promoter 1. In summary, our findings provide additional insights into the role of NF-kappa B transcriptional regulation in hippocampus following status epilepticus and suggest that NF-kappa B pathway activation contributes to seizure susceptibility.