Bioactivity-Guided Isolation of GABA_A Receptor Modulating Constituents from the Rhizomes of Actaea racemosa

Abstract

Black cohosh (Actaea racemosa) is a frequently used herbal remedy for the treatment of mild climacteric symptoms. In the present study, the modulation of γ-aminobutryic acid (GABA)-induced chloride currents (I(GABA)) through GABA type A (GABA(A)) receptors by black cohosh extracts and isolated compounds was investigated. GABA(A) receptors, consisting of α(1), β(2), 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 plant terpenoid fractions, resulting in the isolation of 11 cycloartane glycosides, of which four significantly (p < 0.05) enhanced I(GABA). The most efficient effect was observed for 23-O-acetylshengmanol 3-O-β-d-xylopyranoside (4, 100 μM), enhancing I(GABA) by 1692 ± 201%, while actein (1), cimigenol 3-O-β-d-xylopyranoside (6), and 25-O-acetylcimigenol 3-O-α-l-arabinopyranoside (8) were significantly less active. In the absence of GABA, only 4 induced small (not exceeding 1% of I(GABA-max)) chloride inward currents through GABA(A) receptors. It is hypothesized 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.

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

“…These variations in chemical structure and polarity obviously can lead to diverging activities, as observed in our earlier study on GABA(A)-receptors, where the effect of 23-O-acetylshengmanol-3-O-β-d-xylopyranoside (2) was exceeding that of actein (1) and 25-O-acetylcimigenol-3-O-α-l-arabinopyranoside (3) by more than the factor 5 [9]. In the present work we also observed clear differences in the activity profile of these three compounds.…”

“…Compounds 5 and 6, which both consist of an underivatized cimigenol scaffold, showed no activity on any of the cell lines tested. Neither did 25-anhydrocimigenol-3-O-α-l-arabinopyranoside (9), which is characterized by the absence of a hydroxy-group in position C-25. Chemical IC 50 values of the four active constituents are given in Table 4 and were calculated in µg/mL to make them better comparable to previous studies [15][16][17][18].…”

“…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].…”

GABAA receptor modulation by piperine and a non-TRPV1 activating derivative

“…Natural products from distinct structural classes including flavonoids [22–25], terpenoids [26–28], sesquiterpenes [29–31], diterpenes [32], triterpene glycosides [33], polyacetylenes [34], (neo)lignans [28,35], alkaloids [3] or (furano)coumarins [36,37] have been shown to modulate GABA A receptors.…”

The Phytochemistry of Cherokee Aromatic Medicinal Plants

“…Although recent evidence suggests the estrogen receptor not to be a target of C. racemosa phytochemical constituents, other biomolecular targets may be involved. Rhizome extracts of C. racemosa have been shown to interact with the serotonin receptor [545], the µ-opioid receptor [546,547] as well as the γ-aminobutryic acid type A (GABA A ) receptors [548]. Modulation of these receptors may contribute to some of the biological effects of C. racemosa extracts.…”