Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

Cell Death Differ. 2014 Jul;21(7):1095-106. doi: 10.1038/cdd.2014.29. Epub 2014 Mar 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Aquaporin 4 / metabolism
  • Blood-Brain Barrier / metabolism
  • CA3 Region, Hippocampal / immunology
  • CA3 Region, Hippocampal / pathology
  • Cell Line
  • Cell Nucleus / metabolism
  • Cyclooxygenase 2 / metabolism
  • Haploinsufficiency
  • Kainic Acid
  • Male
  • Mice, Inbred ICR
  • NF-kappa B / physiology*
  • Seizures / chemically induced
  • Seizures / immunology
  • Seizures / metabolism*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Aqp4 protein, mouse
  • Aquaporin 4
  • NF-kappa B
  • Nfat5 protein, mouse
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Kainic Acid