Celecoxib Ameliorates Seizure Susceptibility in Autosomal Dominant Lateral Temporal Epilepsy

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Lin ZhouYing Shen

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 corti...Continue Reading

Citations

Oct 30, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Anika M S HartzBjoern Bauer
Dec 7, 2018·Expert Opinion on Investigational Drugs·Ashish Dhir
Oct 27, 2020·Epilepsia·Eleonora LugaràMatthew C Walker
Dec 12, 2020·The European Journal of Neuroscience·Iman Imtiyaz Ahmed Juvale, Ahmad Tarmizi Che Has
Dec 31, 2021·Cellular and Molecular Life Sciences : CMLS·Paul BaudinVincent Navarro

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