Inhibition of resurgent Na plus currents by rufinamide

Na+ channels are essential for the genesis of action potentials in most neurons. After opening by membrane depolarization, Na+ channels enter a series of inactivated states (e.g. the fast, intermediate, and slow inactivated states; or If, Ii, and Is). The inactivated Na+ channel may recover via the open state upon membrane repolarization, giving rise to "resurgent" Na+ currents which could be critical for densely repetitive or burst discharges. We incubated CHO-K1 cells transfected with human NaV1.7 cDNA and measured resurgent currents with wholecell patch recordings. We found Ii is the major inactivated state responsible for the genesis of resurgent currents. Rufinamide, in therapeutic concentrations, could selectively bind to Ii to slow the recovery process and dosedependently inhibit resurgent currents. The other Na+ channel-inhibiting antiseizure medications (ASM), such as phenytoin and lacosamide (selectively binds to If and Is, separately), fail to show a similar inhibitory effect in clinically relevant concentrations. Resurgent currents are decreased with lengthening of the prepulse, presumably because of redistribution of the channel from Ii to If. Rufinamide could accentuate the decrease to mimic a use-dependent inhibitory effect. The molecular action of slowing of recovery from inactivation by binding to Ii also explains the highly correlative inhibitory effect of rufinamide on both transient and resurgent Na+ currents. The modest but correlative inhibition of both currents may make a novel synergistic effect and thus strongenough suppression of pathological repetitive and especially burst discharges. Rufinamide may thus have a unique spectrum of therapeutic applications for disorders with excessive neural excitabilities.