In vitro and in vivo anti‐epileptic efficacy of eslicarbazepine acetate in a mouse model of KCNQ2‐related self‐limited epilepsy

Abstract

Background and Purpose The KCNQ2 gene encodes for the Kv7.2 subunit of non‐inactivating potassium channels. KCNQ2‐related diseases range from autosomal dominant neonatal self‐limited epilepsy, often caused by KCNQ2 haploinsufficiency, to severe encephalopathies caused by KCNQ2 missense variants. In vivo and in vitro effects of the sodium channel blocker eslicarbazepine acetate (ESL) and eslicarbazepine metabolite (S‐Lic) in a mouse model of self‐limited neonatal epilepsy as a first attempt to assess the utility of ESL in the KCNQ2 disease spectrum was investigated. Experimental Approach Effects of S‐Lic on in vitro physiological and pathological hippocampal neuronal activity in slices from mice carrying a heterozygous deletion of Kcnq2 (Kcnq2+/−) and Kcnq2+/+ mice were investigated. ESL in vivo efficacy was investigated in the 6‐Hz psychomotor seizure model in both Kcnq2+/− and Kcnq2+/+ mice. Key Results S‐Lic increased the amplitude and decreased the incidence of physiological sharp wave–ripples in a concentration‐dependent manner and slightly decreased gamma oscillations frequency. 4‐Aminopyridine‐evoked seizure‐like events were blocked at high S‐Lic concentrations and substantially reduced in incidence at lower concentrations. These results were not different in Kcnq2+/+ and Kcnq2+/− mice, although the EC50 estimation implicated higher efficacy in Kcnq2+/−animals. In vivo, Kcnq2+/− mice had a lower seizure threshold than Kcnq2+/+ mice. In both genotypes, ESL dose‐dependently displayed protection against seizures. Conclusions and Implications S‐Lic slightly modulates hippocampal oscillations and blocks epileptic activity in vitro and in vivo. Our results suggest that the increased excitability in Kcnq2+/− mice is effectively targeted by S‐Lic high concentrations, presumably by blocking diverse sodium channel subtypes.

Adjunctive Treatment With Eslicarbazepine Acetate for Adults and Children With Focal-Onset Epilepsy: A Meta-Analysis

“…An early study in amygdala kindling model of temporal lobe epilepsy in mice showed that ESL dose-dependently increased threshold of focal seizure (29). Using a mouse model of KCNQ2-related epilepsy, a recent study showed that ESL could dose-dependently exert the protection efficacy from seizure (30). However, it has to be mentioned that the result of inefficacy of the 400 mg dosage cannot be generalized because in special populations as in elderly people with epilepsy, ESL of 400 mg dosage can be effective in controlling seizures (31,32).…”

Mouse models of Kcnq2 dysfunction

“…Thresholds for clonic, tonic, or psychomotor (partial) seizures were determined in Kcnq2 mouse models and compared to WT mice. Heterozygous Szt1 , Kcnq2 A306T/+ , and Kcnq2 +/− animals showed a lower seizure threshold compared to their WT counterparts 16,20,34,48 . Of interest, the seizure threshold was lower for mutant and WT females compared to males of the same genotype, suggesting that the seizure threshold is genotype and gender dependent 16,48 .…”

“…Heterozygous Szt1, Kcnq2 A306T/+ , and Kcnq2 +/− animals showed a lower seizure threshold compared to their WT counterparts. 16,20,34,48 Of interest, the seizure threshold was lower for mutant and WT females compared to males of the same genotype, suggesting that the seizure threshold is genotype and gender dependent. 16,48 Currently, no patient study in the literature documents a difference for the epileptic phenotype between men and women for KCNQ2-related disorders.…”

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders

“…KCNQ2 is most expressed in the fetal cerebellum, hippocampus, and medulla [ 30 , 31 ]. Genetic mutation in KCNQ2 is often associated with benign familial neonatal seizures and early-onset epileptic encephalopathy [ 9 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. KCNQ3 is also most expressed in the fetal cerebellum, hippocampus, and medulla [ 9 , 30 ].…”

“…This plays a key role in maintaining the K + gradient for channel mechanosensation to carry K + into hair cells to stimulate auditory sensation [ 14 , 38 ]. KCNQ4 mutations are often associated with auditory hearing loss and have therefore been a key target in developing pharmacotherapeutic options for hearing loss [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. KCNQ5 is most expressed in neural tissue, including the retinal pigment epithelium [ 48 ].…”