Inhibition of resurgent Na⁺ 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 I_f, I_i, and I_s). 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 Na_V1.7 cDNA and measured resurgent currents with whole-cell patch recordings. We found I_i is the major inactivated state responsible for the genesis of resurgent currents. Rufinamide, in therapeutic concentrations, could selectively bind to I_i to slow the recovery process and dose-dependently inhibit resurgent currents. The other Na⁺ channel-inhibiting antiseizure medications (ASM), such as phenytoin and lacosamide (selectively binds to I_f and I_s, 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 I_i to I_f. Rufinamide could accentuate the decrease to mimic a use-dependent inhibitory effect. The molecular action of slowing of recovery from inactivation by binding to I_i 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 strong-enough suppression of pathological repetitive and especially burst discharges. Rufinamide may thus have a unique spectrum of therapeutic applications for disorders with excessive neural excitabilities.