An investigation of the differential effects of ursane triterpenoids from Centella asiatica, and their semisynthetic analogues, on GABA_A receptors

The ursane triterpenoids, asiatic acid 1 and madecassic acid 2, are the major pharmacological constituents of Centella asiatica, commonly known as Gotu Kola, which is used traditionally for the treatment of anxiety and for the improvement of cognition and memory. Using the two-electrode voltage-clamp technique, these triterpenes, and some semisynthetic derivatives, were found to exhibit selective negative modulation of different subtypes of the GABA_A receptor expressed in Xenopus laevis oocytes. Despite differing by only one hydroxyl group, asiatic acid 1 was found to be a negative modulator of the GABA-induced current at α₁β₂γ_2L, α₂β₂γ_2L and α₅β₃γ_2L GABA_A receptors, while madecassic acid 2 was not. Asiatic acid 1 exhibited the greatest effect at α₁β₂γ_2L (IC₅₀ 37.05 μm), followed by α₅β₃γ_2L (IC₅₀ 64.05 μm) then α₂β₂γ_2L (IC₅₀ 427.2 μm) receptors. Conversion of the carboxylic acid group of asiatic acid 1 to a carboxamide group (2α,3β,23-trihydroxy-urs-12-en-28-amide 5) resulted in enhanced inhibition at both the α₁β₂γ_2L (IC₅₀ 14.07 μm) and α₂β₂γ_2L receptor subtypes (IC₅₀ 28.41 μm). The results of this study, and the involvement of α₅-containing GABA_A receptors in cognition and memory, suggest that asiatic acid 1 may be a lead compound for the enhancement of cognition and memory.