Valnoctamide enhances phasic inhibition: a potential target mechanism for the treatment of benzodiazepine-refractory status epilepticus

Valnoctamide (VCD), a derivative of valproate, suppresses electrographic seizures in animal models of status epilepticus (SE), even when the seizures are resistant to benzodiazepines (BZDs). We therefore tested the effect of VCD on miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal cells to determine if VCD acts directly on γ-aminobutyric acid (GABA)A receptors. Bath-applied VCD induced a specific, rapid, dose-dependent, and reversible slowing of the decay of mIPSCs (i.e., increased time constant) with no effect on their frequency or amplitude. This is similar to the effect of BZDs on mIPSCs, but the effect of VCD persisted in the presence of the BZD-binding site antagonist flumazenil, and was additive to the effect of the BZD, diazepam. These data suggest that VCD acts through a different binding site than that of BZDs, which likely accounts for its effect on BZD-refractory SE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.