The contribution of Na_V1.6 to the efficacy of voltage-gated sodium channel inhibitors in wild type and Na_V1.6 gain-of-function (GOF) mouse seizure control

Background and purpose: Inhibitors of voltage-gated sodium channels (Na_Vs) 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_V1.6 alone or together with Na_V1.2. 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_V1.6) and in wild-type mice.

Key results: Pharmacologic inhibition of Na_V1.6 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_V1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS Na_V isoforms.

Conclusions and implications: Our data suggest Na_V1.6 inhibition is a driver of efficacy for Na_V inhibitor anti-seizure medicines. Sparing the Na_V1.1 channels of inhibitory interneurons did not compromise efficacy. Selective Na_V1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies.