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 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. 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.

• Authors: Laura Monni, Larissa Kraus, Matthias Dipper-Wawra, Patricio Soares-da-Silva, Nikolaus Maier, Dietmar Schmitz, Martin Holtkamp, Pawel Fidzinski
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 1 Pg. 84-102 (01 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 34605012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Chemical References

• Anticonvulsants
• Dibenzazepines
• KCNQ2 Potassium Channel
• eslicarbazepine acetate

Topics

• Animals
• Anticonvulsants (pharmacology, therapeutic use)
• Dibenzazepines
• Epilepsy (drug therapy)
• Epilepsy, Temporal Lobe (drug therapy)
• KCNQ2 Potassium Channel (genetics, metabolism)
• Mice
• Seizures (drug therapy)