Abstracts

Rationale: Retigabine (RTG) is the first antiepileptic drug (AED) to activate (open) voltage-gated neuronal KCNQ (Kv7.2-Kv7.5) channels and enhance M-current. It has demonstrated potent activity in a broad array of seizure/epilepsy models, including models in which other AEDs (eg, lamotrigine, carbamazepine, phenytoin, topiramate, levetiracetam) are not active. Linopirdine and XE-991 are KCNQ antagonists that block M-current and therefore serve as specific molecular probes to differentiate potassium currents conducted by KCNQ channels from other currents. In vitro electrophysiologic studies have shown that the KCNQ antagonists linopirdine and XE-991 block RTG-induced increases in M-current. This is the first study designed to evaluate the in vivo contribution of KCNQ-mediated M-current in the anticonvulsant activity of RTG by using a potent KCNQ blocker, i.e., XE-991. Methods: Adult male CF-1 albino mice (N=8 per group) were injected intraperitoneally with RTG 10 mg/kg only; XE-991 3 mg/kg only; or co-injections of RTG 10 mg/kg and XE-991 0.3, 1.0 or 3.0 mg/kg. Animals were injected 15 min before testing. In MES testing, a 60-Hz alternating current (50 mA) was delivered for 0.2 seconds using corneal electrodes, which successfully induces seizures (hind limb tonic extension) in 99-100% of control animals. Lack of tonic extension indicates protection from seizures. Results: MES elicited seizures in all control mice and mice injected with XE-991 only. RTG 10 mg/kg protected 100% of mice from MES-induced seizures. RTG-induced protection was dose-dependently reversed by XE-991. Conclusions: Dose-dependent blockade of RTG activity by the KCNQ channel antagonist XE-991 implies that RTG and XE-991 are acting on the same molecular target. Based on these findings, KCNQ activation is the predominant mechanism of RTG’s antiseizure activity. Funded by Valeant Pharmaceuticals International.