Abstract
23-O-acetylshengmanol-3-O-β-d-xylopyranoside (Ac-SM) isolated from Actaea racemosa L. - an herbal remedy for the treatment of mild menopausal disorders- has been recently identified as a novel efficacious modulator of γ-aminobutyric acid (GABA) type A (GABAA) receptors composed of α1-, β2- and γ2S-subunits. In the present study, we analyzed a potential subunit-selective modulation of GABA-induced chloride currents (IGABA EC3-8) through nine GABAA receptor isoforms expressed in Xenopus laevis oocytes by Ac-SM with 2-microelectrode-voltage-clamp and behavioral effects 30 min after intraperitoneal application in a mouse model. Efficacy of IGABA enhancement by Ac-SM displayed a mild α-subunit-dependence with α2β2γ2S (maximal IGABA potentiation Emax=1454±97%) and α5β2γ2S (Emax=1408±87%) receptors being most efficaciously modulated, followed by slightly weaker IGABA enhancement through α1β2γ2S (Emax=1187±166%), α3β2γ2S (Emax=1174±218%) and α6β2γ2S (Emax=1171±274%) receptors and less pronounced effects on receptors composed of α4β2γ2S (Emax=752±53%) subunits, while potency was not affected by the subunit composition (EC50 values ranging from α1β2γ2S=35.4±12.3µM to α5β2γ2S=50.9±11.8µM). Replacing β2- by β1- or β3-subunits as well as omitting the γ2S-subunit affected neither efficacy nor potency of IGABA enhancement by Ac-SM. Ac-SM shifted the GABA-concentration-response-curve towards higher GABA sensitivity (about 3-fold) and significantly increased the maximal GABA response by 44±13% indicating pharmacological profile distinct from a pure allosteric GABAA receptors modulator. In mice, Ac-SM significantly reduced anxiety-related behavior in the elevated-plus-maze-test at a dose of 0.6mg/kg, total ambulation in the open-field-test at doses ≥6mg/kg, stress-induced hyperthermia at doses ≥0.6mg/kg, and significantly elevated seizure threshold at doses ≥20mg/kg bodyweight. High efficacy and long biological half-life of Ac-SM suggest that potential cumulative sedative side effects upon repetitive intake of Actaea racemosa L. preparations might not be negligible.
- The American Society for Pharmacology and Experimental Therapeutics