NaV1.6 inhibition drives the efficacy of voltage-gated sodium channel inhibitors to prevent electrically induced seizures in both wild type and Scn8aN1768D/+ gain-of-function mice
Johnson, J.; Focken, T.; Tari, P. K.; Dube, C.; Goodchild, S. J.; Andrez, J.-C.; Bankar, G.; Burford, K.; Chang, E.; Chowdhury, S.; Christabel, J.; Dean, R. A.; de Boer, G.; Dehnhardt, C.; Gong, W.; Grimwood, M.; Hussainkhel, A.; Jia, Q.; Khakh, K.; Lee, S.; Li, J.; Lin, S.; Lindgren, A.; Lofstrand, V.; Mezeyova, J.; Nelkenbrecher, K.; Shuart, N. G.; Sojo, L.; Sun, S.; Waldbrook, M.; Wesolowski, S.; Wilson, M.; Xie, Z.; Zenova, A.; Zhang, W.; Scott, F.; Cutts, A. J.; Sherrington, R. P.; Winquist, R.; Cohen, C. J.; Empfield, J. R.
Show abstract
Inhibitors of voltage-gated sodium channels (NaVs) 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 NaV1.6 alone or together with NaV1.2. Mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding NaV1.6) responded with a tonic-clonic seizure to a mild 6 Hz stimulus that was innocuous to wild-type mice. Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti-seizure medicines. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and better tolerated treatments for idiopathic epilepsies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/551823v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@39c09borg.highwire.dtl.DTLVardef@19413b8org.highwire.dtl.DTLVardef@9aa226org.highwire.dtl.DTLVardef@b9207_HPS_FORMAT_FIGEXP M_FIG C_FIG
Matching journals
The top 1 journal accounts for 50% of the predicted probability mass.