Na_V1.6 inhibition drives the efficacy of voltage-gated sodium channel inhibitors to prevent electrically induced seizures in both wild type andScn8a^N1768D/+gain-of-function mice

Abstract Inhibitors of voltage-gated sodium channels (Na V s) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are nonselective. We created a series of compounds with diverse selectivity profiles enabling block of Na V 1.6 alone or together with Na V 1.2. Mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding Na V 1.6) responded with a tonic-clonic seizure to a mild 6 Hz stimulus that was innocuous to wild-type mice. Pharmacologic inhibition of Na V 1.6 in Scn8a N1768D/+ mice prevented seizures. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. Na V 1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS Na V isoforms. Our data suggest Na V 1.6 inhibition is a driver of efficacy for Na V inhibitor anti-seizure medicines. Selective Na V 1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and better tolerated treatments for idiopathic epilepsies. Graphical Abstract