In vitro effects of eslicarbazepine (S-licarbazepine) as a potential precision therapy on SCN8A variants causing neuropsychiatric disorders


Bayraktar E., Liu Y., Sonnenberg L., Hedrich U. B. S., Sara Y., Eltokhi A., ...More

British Journal of Pharmacology, 2022 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Publication Date: 2022
  • Doi Number: 10.1111/bph.15981
  • Journal Name: British Journal of Pharmacology
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, CINAHL, EMBASE, MEDLINE, Veterinary Science Database
  • Keywords: developmental and epileptic encephalopathy, epilepsy, eslicarbazepine, NaV1.6, precision medicine, S-licarbazepine, SCN8A, sodium channel blocker
  • Hacettepe University Affiliated: Yes

Abstract

© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.Background and Purpose: Variants in SCN8A, the NaV1.6 channel's coding gene, are characterized by a variety of symptoms, including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, autistic features, ataxia or dystonia. Standard anticonvulsant treatment has a limited impact on the course of disease. Experimental Approach: We investigated the therapeutic potential of eslicarbazepine (S-licarbazepine; S-lic), an enhancer of slow inactivation of voltage gated sodium channels, on two variants with biophysical and neuronal gain-of-function (G1475R and M1760I) and one variant with biophysical gain-of-function but neuronal loss-of-function (A1622D) in neuroblastoma cells and in murine primary hippocampal neuron cultures. These three variants cover the broad spectrum of NaV1.6-associated disease and are linked to representative phenotypes of mild to moderate epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key Results: Similar to known effects on NaV1.6 wildtype channels, S-lic predominantly enhances slow inactivation on all tested variants, irrespective of their particular biophysical mechanisms. Beyond that, S-lic exhibits variant-specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D and M1760I) and a trend to reduce enhanced persistent Na+ current by A1622D variant channels. Furthermore, our data in primary transfected neurons reveal that not only variant-associated hyperexcitability (M1760I and G1475R) but also hypoexcitability (A1622D) can be modulated by S-lic. Conclusions and Implications: S-lic has not only substance-specific effects but also variant-specific effects. Personalized treatment regimens optimized to achieve such variant-specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A-related disease.