Neuroprotective agent riluzole potentiates postsynaptic GABA_A receptor function

The antiepileptic drug riluzole is a use-dependent blocker of voltage-gated Na⁺ channels and selectively depresses action potential-driven glutamate over γ-aminobutyric acid (GABA) release. Here we report that in addition to its presynaptic effect, riluzole at higher concentrations also strongly potentiates postsynaptic GABA_A responses both in cultured hippocampal neurons and in Xenopus oocytes expressing recombinant receptors. Although peak inhibitory postsynaptic currents (IPSCs) of autaptic hippocampal neurons were inhibited, 20-100 μM riluzole significantly prolonged the decay of IPSCs, resulting in little change in total charge transfer. The effect was dose-dependent and reversible. Riluzole selectively increased miniature IPSC fast and slow decay time constants, without affecting their relative proportions. Miniature IPSC peak amplitude, rise time and frequency were unaffected, indicating a postsynaptic mechanism. In the Xenopus oocyte expression system, riluzole potentiated GABA responses by lowering the EC₅₀ for GABA activation. Riluzole directly gated a GABA_A current that was partially blocked by bicuculline and gabazine. Pharmacological experiments suggest that the action of riluzole did not involve a benzodiazepine, barbiturate, or neurosteroid site. Instead, riluzole-induced potentiation was inhibited by the lactone antagonist α-isopropyl-α-methyl-γ-butyrolatone (α-IMGBL). While most anticonvulsants either block voltage-gated Na⁺ channels or potentiate GABA_A receptors, our results suggest that riluzole may define an advantageous class of anticonvulsants with both effects.