Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures.
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Cell death and differentiation, ISSN: 1476-5403, Vol: 21, Issue: 7, Page: 1095-106
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- Biochemistry, Genetics and Molecular Biology; TRANSCRIPTION FACTOR NFAT5; TEMPORAL-LOBE EPILEPSY; STATUS EPILEPTICUS; BRAIN-DAMAGE; RAT-BRAIN; SYSTEMIC HYPERTONICITY; MOUSE HIPPOCAMPUS; WATER CHANNELS; NEURONAL DEATH; EXPRESSION
Kainic acid (KA)-induced seizures followed by neuronal death are associated with neuroinflammation and blood-brain barrier (BBB) leakage. Tonicity-responsive enhancer binding protein (TonEBP) is known as a transcriptional factor activating osmoprotective genes, and in brain, it is expressed in neuronal nuclei. Thus dysregulation of TonEBP may be involved in the pathology of KA-induced seizures. Here we used TonEBP heterozygote (+/-) mice to study the roles of TonEBP. Electroencephalographic study showed that TonEBP (+/-) mice reduced seizure frequency and severity compared with wild type during KA-induced status epilepticus. Immunohistochemistry and western blotting analysis showed that KA-induced neuroinflammation and BBB leakage were dramatically reduced in TonEBP (+/-) mice. Similarly, TonEBP-specific siRNA reduced glutamate-induced death in HT22 hippocampal neuronal cells. TonEBP haplodeficiency prevented KA-induced nuclear translocation of NF-κB p65 and attenuated inflammation. Our findings identify TonEBP as a critical regulator of neuroinflammation and BBB leakage in KA-induced seizures, which suggests TonEBP as a good therapeutic target.