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

Cicek, SS; Khom, Sophia; Taferner, Barbara; Hering, S; Stuppner, Hermann

doi:10.1055/s-0031-1282155

Cited by 9 publications

(22 citation statements)

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“…CR extract reportedly acts as a competitive ligand and a partial agonist for opiate receptors (41,42), similar to 5-HT receptors. Additionally, CR extract and isolated cycloartane glycosides have gamma-aminobutyric acid (GABA) A receptor-modulating effects (12), which could also be relevant to the present results. Thus far, little is known about the pharmacokinetics and metabolites of CR extract.…”

Section: Discussionsupporting

confidence: 58%

Oral administration of Cimicifuga racemosa extract attenuates psychological and physiological stress responses

et al. 2012

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Section: Discussionsupporting

confidence: 58%

Oral administration of Cimicifuga racemosa extract attenuates psychological and physiological stress responses

et al. 2012

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“…Ac-SM efficaciously potentiates I GABA through GABA A receptors composed of a 1 b 2 g 2S subunits (Cicek et al, 2010). As illustrated in Fig.…”

Section: Resultsmentioning

confidence: 83%

“…3). Ac-SM at 300 mM induced only small currents in the absence of GABA (not exceeding 1% of maximal I GABA induced by 1 mM GABA), indicating modulatory effects (see also Cicek et al, 2010).…”

Section: Ac-sm Shifts the Gaba Concentration-responsementioning

confidence: 82%

“…Ac-SM ( Fig. 1) was isolated from A. racemosa L. as previously described (Cicek et al, 2010). Stock solutions (100 mM for in vitro experiments and 1 mg/10 ml for in vivo experiments, respectively) were prepared in dimethylsulfoxide (DMSO).…”

Section: Methodsmentioning

confidence: 99%

“…GABA A receptors are modulated by structurally diverse compounds including clinically applied drugs, such as benzodiazepines, barbiturates, neurosteroids, and anesthetics, as well as a large number of natural products, including flavonoids, terpenoids, or polyacetlyenes (for review, see Johnston et al, 2006;Olsen and Sieghart, 2009;Hanrahan et al, 2011;Nilsson and Sterner, 2011). Recently, we have identified four cycloartane glycosides (actein, cimigenol 3-O-b-D-xylopyranoside, 25-O-acetylcimigenol 3-O-a-L-arabinopyranoside, and 23-O-acetylshengmanol 3-Ob-D-xylopyranoside) as novel efficacious GABA A modulators isolated from Actaea racemosa L. Whereas enhancement of GABA-induced chloride currents (I GABA ) by actein, cimigenol 3-O-b-D-xylopyranoside, and 25-O-acetylcimigenol 3-O-a-Larabinopyranoside averaged at about 300%, a more than 5-fold stronger I GABA potentiation was observed for cycloartane glycoside 23-O-acetylshengmanol 3-O-b-D-xylopyranoside (Ac-SM) (Cicek et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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

Strommer¹,

Khom²,

Kastenberger³

et al. 2014

J Pharmacol Exp Ther

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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.

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Chemical and biological studies of Cimicifugeae pharmaceutical resources

Hao¹,

Gu²,

Xiao³

2015

Medicinal Plants

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

Cited by 9 publications

References 0 publications

Oral administration of Cimicifuga racemosa extract attenuates psychological and physiological stress responses

Oral administration of Cimicifuga racemosa extract attenuates psychological and physiological stress responses

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

Chemical and biological studies of Cimicifugeae pharmaceutical resources

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

Cited by 9 publications

References 0 publications

Oral administration of Cimicifuga racemosa extract attenuates psychological and physiological stress responses

Oral administration of Cimicifuga racemosa extract attenuates psychological and physiological stress responses

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

Chemical and biological studies of Cimicifugeae pharmaceutical resources

Contact Info

Product

Resources

About

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