Carisbamate, a novel neuromodulator, inhibits voltage-gated sodium channels and action potential firing of rat hippocampal neurons

Summary 

Carisbamate (RWJ-333369; (S)-2-O-carbamoyl-1-o-chlorophenyl-ethanol) is a novel investigational antiepileptic drug that exhibits a broad-spectrum of activity in a number of animal models of seizure and drug refractory epilepsy. In an effort to understand the molecular mechanism by which carisbamate produces its antiepileptic actions, we studied its effects on the function of voltage-gated, rat brain sodium and potassium channels and on the repetitive firing of action potentials in cultured rat hippocampal neurons. In whole-cell patch clamp recording, carisbamate resulted in a concentration-, voltage- and use-dependent inhibition of rat Nav1.2, with an IC₅₀ value of 68μM at −67mV. In rat hippocampal neurons, carisbamate similarly blocked voltage-gated sodium channels, with an IC₅₀ value of 89μM at −67mV, and inhibited repetitive firing of action potentials in a concentration-dependent manner (by 46% at 30μM and 87% at 100μM, respectively). Carisbamate had no effect on the steady-state membrane potential or voltage-gated potassium channels (K_v) in these neurons. These inhibitory effects of carisbamate occurred at therapeutically relevant concentrations in vivo, raising the possibility that block of voltage-gated sodium channels by carisbamate contributes to its antiepileptic activity.

Keywords: RWJ-333369, Antiepileptic drug, Patch clamp, Nav1.2, Sodium channel