Effects of bilobalide, ginkgolide B and picrotoxinin on GABAA receptor modulation by structurally diverse positive modulators

Anxiolytics and anticonvulsants generally positively modulate the action of GABA, whereas many convulsants (including the Chloride Channel blocker picrotoxinin) negatively modulate the action of GABA on GABA_A receptors. Like picrotoxinin, bilobalide and ginkgolide B, active constituents of Ginkgo biloba, have been shown to negatively modulate the action of GABA at α₁β₂γ_2L GABA_A receptors. However, unlike picrotoxinin, bilobalide and ginkgolide B are not known to cause convulsions. We have assessed the action of bilobalide, ginkgolide B and picrotoxinin on a range of GABA_A modulators (etomidate, loreclezole, propofol, thiopentone sodium, diazepam, and allopregnanolone), using two-electrode voltage clamp electrophysiology at recombinant α₁β₂γ_2L GABA_A receptors expressed in Xenopus oocytes. The results indicate that bilobalide and ginkgolide B differ from picrotoxinin in their ability to inhibit the actions of a range of these structurally diverse GABA_A positive modulators consistent with these modulators acting on a multiplicity of active sites associated with GABA_A receptors. In the presence GABA, ginkgolide B was more potent than bilobalide in inhibiting the GABA-potentiating effect of propofol, equipotent against loreclezole and allopregnanolone, and less potent against etomidate, diazepam, and thiopentone sodium. This indicates that in comparison to picrotoxinin, bilobalide and ginkgolide B differ in their effects on the different modulators.