Selective stabilization of the intermediate inactivated Na < sup > + < /sup > channelby new-generation anticonvulsant rufinamide

Biochem Pharmacol. 2022 Jan 18:114928. doi: 10.1016/j.bcp.2022.114928. Online ahead of print.ABSTRACTNa+ channels undergo multiple inactivated states with different kinetics, which set the refractory period of neuronal discharges, but isolating the intermediate inactivated state has been challenging. Most classical Na+channel-inhibiting anticonvulsants bind to the fast inactivated state to reduce Na+currents and cellular excitability. The slow binding kinetics necessitates long depolarization for drug action, a "use-dependent" effect sparing most normal activities. Rufinamide is a new anticonvulsant targeting Na+channels, and has a therapeutic effect on Lennox-Gastaut syndrome (LGS) which is refractory to classicalNa+channel inhibitors. The efficacy on LGS, whose epileptiform discharges largely involve short depolarization or bursts, is primarily due to very fast binding kinetics of rufinamide. Could the very fast kinetics of rufinamide lead to indiscriminate inhibition of Na+currents? Onhippocampal neurons from male and female mice, wefound that rufinamide most effectively shifts the Na+channel inactivation curve if the inactivating pulse is 1 s, but not 0.1 or 18 s, in duration. Rufinamide also shows a maximal slowing effect on the recovery kinetics from the inactivation driven by modest depolarization (e.g. -60 mV) of intermediate length (e.g. 50-300 ms). Consistently, rufinamide selectively inhibits the burst discharges at 50-300 ms on a plateau of ∼-60 mV. This is mech...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research