Bioactivity-guided Isolation of GABAA Receptor Modulating Constituents from the Rhizome of Actaea racemosa

Black cohosh (Actaea racemosa Walter ex Steud.) is a frequently used herbal remedy for the treatment of mild climacteric symptoms. The plants active principle was extensively studied, but its mechanism of action remained unclear [1]. In this study the modulation of GABA-induced chloride currents (I_GABA) through GABA_A receptors by black cohosh extracts and isolated compounds was investigated. GABA_A-receptors consisting of α₁, β₂ and γ_2S subunits were expressed in Xenopus laevis oocytes and potentiation of I_GABA was measured using the two-microelectrode voltage clamp technique. In a bioactivity-guided isolation procedure the positive modulation of I_GABA could be restricted to the terpenoid fractions, resulting in the isolation of 11 cycloartane glycosides, of which 4 compounds significantly enhanced I_GABA by more than 150% (p<0.05). The strongest effect was observed for 23-O-acetylshengmanol-3-O-β-D-xylopyranoside (100µM) enhancing I_GABA by 1692±201%, while actein, cimigenol-3-O-β-D-xylopyranoside and 25-O-acetylcimigenol-3-O-α-L-arabinopyranoside were significantly less efficient (range of I_GABA enhancement at 100µM: 256±40% –378±64%). 23-O-acetylshengmanol-3-O-β-D-xylopyranoside, which exhibited the greatest potentiation of I_GABA, was additionally investigated in a mouse model. In these studies a decrease in motoractivity as well as a clear reduction in anxiety behaviour of animals treated with 23-O-acetylshengmanol-3-O-β-D-xylopyranoside was observed, indicating this compound to induce strong sedative effects with concomitant anxiolytic activity. We hypothesise that the established positive allosteric modulation of GABA_A receptors may contribute to beneficial effects of black cohosh extracts in the treatment of climacteric symptoms.

References: 1. Palacio C, Masri G (2009) Drugs Aging 2623–36.