Potentiating effect of glabridin from Glycyrrhiza glabra on GABA(A) receptors

Extracts from Glycyrrhiza are traditionally used for the treatment of insomnia and anxiety. Glabridin is one of the main flavonoid compounds from Glycyrrhiza glabra and displays a broad range of biological properties. In the present work, we investigated the effect of glabridin on GABA(A) receptors. For this purpose, we employed the two-electrode voltage-clamp technique on Xenopus laevis oocytes expressing recombinant GABA(A) receptors. Through this approach, we observed that glabridin presents a strong potentiating effect on GABA(A) α1β(1−3)γ2 receptors. The potentiation was slightly dependent on the β subunit and was most pronounced at the α1β2γ2 subunit combination, which forms the most abundant GABA(A) receptor in the CNS. Glabridin potentiated with an EC(50) of 6.3±1.7 µM and decreased the EC(50) of the receptor for GABA by approximately 12-fold. The potentiating effect of glabridin is flumazenil-insensitive and does not require the benzodiazepine binding site. Glabridin acts on the β subunit of GABA(A) receptors by a mechanism involving the M286 residue, which is a key amino acid at the binding site for general anesthetics, such as propofol and etomidate. Our results demonstrate that GABA(A) receptors are strongly potentiated by one of the main flavonoid compounds from Glycyrrhiza glabra and suggest that glabridin could contribute to the reported hypnotic effect of Glycyrrhiza extracts.