In vitro and in vivo antiepileptic efficacy of eslicarbazepine acetate in a mouse model of KCNQ2-related self-limited epilepsy.

BACKGROUND AND PURPOSE The KCNQ2 gene encodes for the Kv 7.2 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. Here, we investigated in vitro and in vivo effects of the sodium channel blocker eslicarbazepine acetate (ESL) in a mouse model of self-limited neonatal epilepsy as a first attempt to assess the utility of ESL in the KCNQ2 disease spectrum. EXPERIMENTAL APPROACH We employed a mouse model carrying a heterozygous deletion of the Kcnq2 gene known to cause self-limited neonatal epilepsy, to test effects of the metabolite eslicarbazepine (S-Lic) on physiological and pathological hippocampal neuronal activity in acute slices in vitro and to investigate ESL efficacy in juvenile mice in vivo in the 6 Hz psychomotor seizure model. 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.