Celecoxib ameliorates seizure susceptibility in autosomal dominant lateral temporal epilepsy

Lin Zhou, Liang Zhou, Li Da Su, Sheng Long Cao, Ya Jun Xie, Na Wang, Chong Yu Shao, Ya Nan Wang, Jia Huan Zhou, John Kenneth Cowell, Ying Shen

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that glutamatergic transmission is altered in LGI1 mutant mice, and seizures can be reduced by restoring LGI1 function. Yet, the mechanism underlying ADLTE is unclear. Here, we propose that seizures in male LGI1-/-mice are due to nonsynaptic epileptiform activity in cortical neurons. We examined the intrinsic excitability of pyramidal neurons in the temporal cortex of male LGI1-/-mice and found that the voltage-gated K+channel Kv1.2 was significantly downregulated. We also found that cytosolic phospholipase A2(cPLA2)-cyclooxygenase 2 (Cox2) signaling was enhanced in LGI1-/-mice. Interestingly, Cox2 inhibition effectively restored the dysregulated Kv1.2 and reduced the intrinsic excitability of pyramidal neurons. Moreover, in vivo injection of celecoxib, an FDA-approved nonsteroidal anti-inflammatory drug, rescued the defective Kv1.2 (an ~1.9-fold increase), thereby alleviating the seizure susceptibility and extending the life of LGI1-/-mice by 5 d. In summary, we conclude that LGI1 deficiency dysregulates cPLA2-Cox2 signaling to cause hyperexcitability of cortical pyramidal neurons, and celecoxib is a potential agent to manage human ADLTE.

Original languageEnglish (US)
Pages (from-to)3346-3357
Number of pages12
JournalJournal of Neuroscience
Volume38
Issue number13
DOIs
StatePublished - Mar 28 2018

Keywords

  • ADLTE
  • Celecoxib
  • Cox2
  • Epilepsy
  • Kv1.2

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Zhou, L., Zhou, L., Su, L. D., Cao, S. L., Xie, Y. J., Wang, N., Shao, C. Y., Wang, Y. N., Zhou, J. H., Cowell, J. K., & Shen, Y. (2018). Celecoxib ameliorates seizure susceptibility in autosomal dominant lateral temporal epilepsy. Journal of Neuroscience, 38(13), 3346-3357. https://doi.org/10.1523/JNEUROSCI.3245-17.2018