Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcription factor nuclear factor-kappaB (NFkappaB) is an ubiquitously expressed inducible regulator of a broad range of genes and plays a pivotal role in cell death and survival pathways. Three models of brain tolerance (ischemic, epileptic, and polyunsaturated fatty acid-induced preconditioning), known to confer resistance to neurons against ischemia or status epilepticus, were used to determine whether NFkappaB mediated the late preconditioning. A sublethal 3 min ischemia, a dose of 5 mg/kg kainic acid (KA5) or 500 nmol of linolenic acid (LIN500) led to a rapid increase of NFkappaB DNA-binding activity and nuclear translocation of p65 and p50 subunits of NFkappaB in neurons. Pretreatment with the NFkappaB inhibitor diethyldithiocarbamate or kappaB decoy DNA blocked the increased DNA-binding activity and the nuclear translocation of NFkappaB and abolished the neuroprotective effects of different delayed preconditionings against severe ischemia or epilepsy. The inhibition of NFkappaB observed in rats preconditioned with 3 min ischemia, KA5 or LIN500 treatments compared with ischemic or epileptic controls was correlated with the prevention of the inducible degradation of the inhibitory protein IkappaBalpha. Preconditioning probably inhibits the activation of NFkappaB by interfering with a pathway that leads to the direct transcriptional activation of IkappaBalpha by NFkappaB itself. The present work provides evidence that activation of NFkappaB is a crucial step in the signal transduction pathway that underlies the development of brain tolerance and may open new strategies in the prevention of cerebral diseases, such as ischemia or epilepsy.
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PMID:Activation of the nuclear factor-kappaB is a key event in brain tolerance. 1142 94

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.
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PMID:Nuclear factor-kappa B regulates seizure threshold and gene transcription following convulsant stimulation. 1772 32

Whereas status epilepticus, or the condition of continuous epileptic seizures, produces a characteristic pattern of preferential neuronal cell loss in the hippocampus, the underlying mechanism is still unsettled. Based on an experimental model of temporal lobe status epilepticus, we demonstrated previously that prolonged seizures prompted an overproduction of nitric oxide (NO) by upregulation of NO synthase II (NOS II) in the hippocampal CA3 subfield, followed by the activation of mitochondrial apoptotic signaling cascade. Using the same animal model, the present study evaluated the hypothesis that transcriptional upregulation of NOS II gene by nuclear factor-kappaB (NF-kappaB) promotes apoptotic neuronal cell death in the hippocampus following status epilepticus. In Sprague-Dawley rats, significantly augmented nucleus-bound translocation of NF-kappaB p50 and p65 subunits and DNA binding activity of NF-kappaB were observed in hippocampal CA3 neurons as early as 30 min after elicitation of sustained seizure activity by microinjection of kainic acid into the CA3 subfield, followed by a progressive elevation that peaked at 90 min. In addition, application bilaterally into the hippocampal CA3 subfield of a selective NF-kappaB inhibitor, pyrrolidine dithiocarbamate or double-stranded kappaB decoy DNA significantly antagonized the activated NOS II-peroxynitrite signaling cascade (3 hr) and the associated manifestations of apoptotic cell death (7 days) in the hippocampus. We conclude that activation of NF-kappaB in hippocampal CA3 neurons upregulates NOS II gene expression following experimental temporal lobe status epilepticus, leading to apoptotic neuronal cell death in the hippocampus.
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PMID:Transcriptional upregulation of nitric oxide synthase II by nuclear factor-kappaB promotes apoptotic neuronal cell death in the hippocampus following experimental status epilepticus. 2015 97