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

Abstract

23-O-Acetylshengmanol 3-O-b-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 GABA A receptors composed of a 1 -, b 2 -, and g 2S -subunits. In the present study, we analyzed a potential subunit-selective modulation of GABAinduced chloride currents (I GABA ) at GABA concentrations eliciting 3-8% of the maximal GABA response (EC 3-8 ) through nine GABA A receptor 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 I GABA enhancement by Ac-SM displayed a mild a-subunit dependence with a 2 b 2 g 2S (maximal I GABA potentiation [E max ] 5 1454 6 97%) and a 5 b 2 g 2S (E max 5 1408 6 87%) receptors being most efficaciously modulated, followed by slightly weaker I GABA enhancement through a 1 b 2 g 2S (E max 5 1187 6 166%) , a 3 b 2 g 2S (E max 5 1174 6 218%), and a 6 b 2 g 2S (E max 5 1171 6 274%) receptors and less pronounced effects on receptors composed of a 4 b 2 g 2S (E max 5 752 6 53%) subunits, whereas potency was not affected by the subunit composition (EC 50 values ranging from a 1 b 2 g 2S 5 35.4 6 12.3 mM to a 5 b 2 g 2S 5 50.9 6 11.8 mM). Replacing b 2 -with b 1 -or b 3 -subunits as well as omitting the g 2S -subunit affected neither efficacy nor potency of I GABA enhancement 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 GABA A receptor 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.

Structure-Guided Identification of Black Cohosh (Actaea racemosa) Triterpenoids with In Vitro Activity against Multiple Myeloma

“…These triterpenoids are characterized by a 9,19-cycloartane group and considered to be the plant's active principle [8]. Because of the hormone-like activity of black cohosh preparations, an estrogen-receptor mediated activity was initially assumed, but the alleviating effects are rather the result of GABA(A)-receptor modulation [9,10]. In the same context, black cohosh triterpenoids actein (1) and 23-epi-26-deoxyactein were found to exhibit beneficial effects against postmenopausal osteoporosis promoting cell growth and differentiation of osteoblast as well as osteocalcin production and mineralization [11][12][13], thus confirming the use of black cohosh for climacteric complaints [14].…”

Chemical and biological studies of Cimicifugeae pharmaceutical resources

“…Ac-SM shifted the GABA concentration-response curve toward higher GABA sensitivity (about threefold) and significantly increased the maximal GABA response by 44 AE 13%, indicating a pharmacological profile distinct from a pure allosteric GABAA receptor modulator (Strommer et al, 2014). Ac-SM shifted the GABA concentration-response curve toward higher GABA sensitivity (about threefold) and significantly increased the maximal GABA response by 44 AE 13%, indicating a pharmacological profile distinct from a pure allosteric GABAA receptor modulator (Strommer et al, 2014).…”

Structure-Dependent Activity of Natural GABA(A) Receptor Modulators

“…Interestingly, cleavage of the pentose moiety led to a significant decrease of activity (especially for compound 231 ). Compound 231 was subsequently subjected to several in vivo studies to examine its anxiolytic and sedative properties [ 168 ]. Compound 231 increased the number of open entries at 0.6 mg/kg in the EPM test and reduced stress-induced hyperthermia at doses of 0.2, 0.6, 2 and 6 mg/kg.…”