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 (122L,222L) and (532L) GABA(A) receptors, while madecassic acid 2 was not. Asiatic acid 1 exhibited the greatest effect at (122L) (IC50 37.05 m), followed by (532L) (IC50 64.05 m) then (222L) (IC50 427.2 m) receptors. Conversion of the carboxylic acid group of asiatic acid 1 to a carboxamide group (2,3,23-trihydroxy-urs-12-en-28-amide 5) resulted in enhanced inhibition at both the (122L) (IC50 14.07 m) and (222L) receptor subtypes (IC50 28.41 m). The results of this study, and the involvement of (5)-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.