A Cycloartane Glycoside Derived from Actaea racemosa L. Modulates GABA(A) Receptors and Induces Pronounced Sedation in Mice

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 GABAreceptors composed of α _1-, β _2-, and γ _2S-subunits. In the present study, we analyzed a potential subunit-selective modulation of ABA-induced chloride currents (I at GABA concentrations eliciting 3-8% of the maximal GABA response (EC through nine GABAreceptor isoforms expressed in Xenopus laevis oocytes by Ac-SM with two-microelectrode voltage clamp and behavioral effects 30 minutes after intraperitoneal application in a mouse model. Efficacy of Ienhancement by Ac-SM displayed a mild a-subunit dependence with α ₂β ₂γ _2S(maximal Ipotentiation [E _max] 5 1454 6 97%) and α ₅β ₂γ _2S(E _max5 1408 6 87%) receptors being most efficaciously modulated, followed by slightly weaker Ienhancement through α ₁β ₂γ _2S(E _max5 1187 6 166%), α ₃β ₂γ _2S(E _max5 1174 6 218%), and a6b2g2S (E _max5 1171 6 274%) receptors and less pronounced effects on receptors composed of a4b2g2S (E _max5 752 6 53%) subunits, whereas potency was not affected by the subunit composition (EC50 values ranging from α ₁β ₂γ _2S535.4612.3 mM to α ₅β ₂γ _2S5 50.9 6 11.8 mM). Replacing b2-with b1-or b3-subunits as well as omitting the g2S-subunit affected neither efficacy nor potency of Ienhancement by Ac-SM. Ac-SM shifted the GABA concentration-response curve toward higher GABA sensitivity (about 3-fold) and significantly increased the maximal GABA response by 44 6 13%, indicating a pharmacological profile distinct from a pure allosteric GABAreceptor modulator. In mice, Ac-SM significantly reduced anxiety-related behavior in the elevated plus maze test at a dose of 0.6 mg/kg, total ambulation in the open field test at doses $6 mg/kg, stressinduced hyperthermia at doses $0.6 mg/kg, and significantly elevated seizure threshold at doses $20 mg/kg body weight. High efficacy and long biologic half-life of Ac-SM suggest that potential cumulative sedative side effects upon repetitive intake of A. racemosa L. preparations might not be negligible. Copyright