Nuclear factor-kappa B regulates seizure threshold and gene transcription following convulsant stimulation.
We evaluated a role for the nuclear factor-kappa B (NF-kappaB) pathway in the regulation of seizure susceptibility and transcriptional activation during prolonged, continuous seizures (status epilepticus). Using two functionally distinct NF-kappaB inhibitors we observed a decrease in latency to onset of kainate-induced seizures and status epilepticus. To assess NF-kappaB transcriptional activation, we evaluated inhibitor kappa B alpha (IkappaBalpha) and brain-derived neurotrophic factor (bdnf) gene targets. Inhibition of the NF-kappaB signaling pathway significantly attenuated the increases in IkappaBalpha and bdnf mRNA levels that occurred during prolonged seizure activity, suggesting that the NF-kappaB 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-kappaB subunits were associated with the candidate kappaB-binding elements within promoter 1 of the bdnf gene. The pattern of association was different for the p50 and p65 subunits supporting complex NF-kappaB modifications within promoter 1. In summary, our findings provide additional insights into the role of NF-kappaB transcriptional regulation in hippocampus following status epilepticus and suggest that NF-kappaB pathway activation contributes to seizure susceptibility.
Lubin
Farah D
FD
Cain Foundation Laboratories, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA, and Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.
Ren
Yajun
Y
Xu
Xianghua
X
Anderson
Anne E
AE
D000818:Animals; D003292:Convulsants / Q000633:toxicity*; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D003292:Convulsants; D016328:NF-kappa B; D007608:Kainic Acid