The contribution of NaV1.6 to the efficacy of voltage‐gated sodium channel inhibitors in wild type and NaV1.6 gain‐of‐function (GOF) mouse seizure control

Background and Purpose 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 non‐selective. We aimed to create novel, isoform selective inhibitors of Na v channels as a means of informing the development of improved antiseizure drugs. Experimental Approach 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. These novel Na V inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain‐of‐function mutation (N1768D/+) in Scn8a (encoding Na V 1.6) and in wild‐type mice. Key Results Pharmacologic inhibition of Na V 1.6 in Scn8a N1768D /+ mice prevented seizures evoked by a 6‐Hz shock. 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. Conclusions and Implications Our data suggest Na V 1.6 inhibition is a driver of efficacy for Na V inhibitor anti‐seizure medicines. Sparing the Na V 1.1 channels of inhibitory interneurons did not compromise efficacy. Selective Na V 1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies.