Rufinamide Modifies the Gating Process of Human Voltage-Gated Sodium Channels

Abstract

Lennox-Gastaut Syndrome (LGS) is a severe form of epilepsy manifesting during early childhood. Treatment of the seizures and the ensuing behavioral and mental health problems commonly associated with LGS requires multiple anticonvulsant therapeutics, often with deleterious effects on the patient. Although the relatively new orphan drug rufinamide is gaining importance as an adjunct therapy for LGS, its mode of action remains speculative. To establish the molecular mechanism underlying rufinamide efficacy, we compared its effect on a subset of neuronal human voltage-gated sodium (Nav) channel isoforms (hNav1.1, hNav1.2, hNav1.3, and hNav1.6), several of which are thought to be involved in epilepsy. As a result, we found that a clinically relevant concentration inhibits hNav1.1 activation whereas the recovery from fast inactivation of hNav1.1, hNav1.2, hNav1.3, and hNav1.6 is slowed down. Moreover, experiments with related triazole compounds revealed drug variants with effects comparable to those of rufinamide and suggest that modifications of particular side chains may be exploited to obtain an isoform-specific drug-induced effect on hNav1.1 activation.