In Vitro Serotonergic Activity of Black Cohosh and Identification of N(omega)-methylserotonin As a Potential Active Constituent

Overview

Journal J Agric Food Chem

Specialties Chemistry
Nutritional Sciences

Date 2008 Dec 4

PMID 19049296

Citations 27

Authors

Sharla L Powell

Tanja Godecke

Dejan Nikolic

Shao-Nong Chen

Soyoun Ahn

Birgit Dietz

Norman R Farnsworth

Richard B van Breemen

David C Lankin

Guido F Pauli

Judy L Bolton

Affiliations

Soon will be listed here.

Abstract

Cimicifuga racemosa (L.) Nutt. (syn. Actaea racemosa L., black cohosh) is used to relieve menopausal hot flashes, although clinical studies have provided conflicting data, and the active constituent(s) and mechanism(s) of action remain unknown. Because serotonergic receptors and transporters are involved with thermoregulation, black cohosh and its phytoconstituents were evaluated for serotonergic activity using 5-HT7 receptor binding, cAMP induction, and serotonin selective re-uptake inhibitor (SSRI) assays. Crude extracts displayed 5-HT7 receptor binding activity and induced cAMP production. Fractionation of the methanol extract led to isolation of phenolic acids and identification of N(omega)-methylserotonin by LC-MS/MS. Cimicifuga triterpenoids and phenolic acids bound weakly to the 5-HT7 receptor with no cAMP or SSRI activity. In contrast, N(omega)-methylserotonin showed 5-HT7 receptor binding (IC50 = 23 pM), induced cAMP (EC50 = 22 nM), and blocked serotonin re-uptake (IC50 = 490 nM). These data suggest N(omega)-methylserotonin may be responsible for the serotonergic activity of black cohosh.

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References

Cox B, Ary M, LOMAX P . Dopaminergic mechanisms in withdrawal hypothermia in morphine dependent rats. Life Sci. 1975; 17(1):41-2. DOI: 10.1016/0024-3205(75)90231-3. View

Rossouw J, Anderson G, Prentice R, LaCroix A, Kooperberg C, Stefanick M . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002; 288(3):321-33. DOI: 10.1001/jama.288.3.321. View

Nuntanakorn P, Jiang B, Einbond L, Yang H, Kronenberg F, Weinstein I . Polyphenolic constituents of Actaea racemosa. J Nat Prod. 2006; 69(3):314-8. DOI: 10.1021/np0501031. View

Burdette J, Liu J, Chen S, Fabricant D, Piersen C, Barker E . Black cohosh acts as a mixed competitive ligand and partial agonist of the serotonin receptor. J Agric Food Chem. 2003; 51(19):5661-70. DOI: 10.1021/jf034264r. View

Rodriguez G, Roman D, White K, Nichols D, Barker E . Distinct recognition of substrates by the human and Drosophila serotonin transporters. J Pharmacol Exp Ther. 2003; 306(1):338-46. DOI: 10.1124/jpet.103.048751. View

Cox B, Tha S . The role of dopamine and noradrenaline in temperature control of normal and reserpine-pretreated mice. J Pharm Pharmacol. 1975; 27(4):242-7. DOI: 10.1111/j.2042-7158.1975.tb10693.x. View

Loprinzi C, Flynn P, Carpenter L, Atherton P, Barton D, Shanafelt T . Pilot evaluation of citalopram for the treatment of hot flashes in women with inadequate benefit from venlafaxine. J Palliat Med. 2005; 8(5):924-30. DOI: 10.1089/jpm.2005.8.924. View

Rossi D, Burke T, McCasland M, Hensler J . Serotonin-1A receptor function in the dorsal raphe nucleus following chronic administration of the selective serotonin reuptake inhibitor sertraline. J Neurochem. 2008; 105(4):1091-9. DOI: 10.1111/j.1471-4159.2007.05201.x. View

Burdette J, Chen S, Lu Z, Xu H, White B, Fabricant D . Black cohosh (Cimicifuga racemosa L.) protects against menadione-induced DNA damage through scavenging of reactive oxygen species: bioassay-directed isolation and characterization of active principles. J Agric Food Chem. 2002; 50(24):7022-8. DOI: 10.1021/jf020725h. View

10.

Chen S, Fabricant D, Lu Z, Zhang H, Fong H, Farnsworth N . Cimiracemates A-D, phenylpropanoid esters from the rhizomes of Cimicifuga racemosa. Phytochemistry. 2002; 61(4):409-13. DOI: 10.1016/s0031-9422(02)00209-1. View

11.

Borrelli F, Izzo A, Ernst E . Pharmacological effects of Cimicifuga racemosa. Life Sci. 2003; 73(10):1215-29. DOI: 10.1016/s0024-3205(03)00378-3. View

12.

Stomati M, Rubino S, Spinetti A, Parrini D, Luisi S, Casarosa E . Endocrine, neuroendocrine and behavioral effects of oral dehydroepiandrosterone sulfate supplementation in postmenopausal women. Gynecol Endocrinol. 1999; 13(1):15-25. DOI: 10.1080/09513599909167527. View

13.

Pauli G, Jaki B, Lankin D . Quantitative 1H NMR: development and potential of a method for natural products analysis. J Nat Prod. 2005; 68(1):133-49. DOI: 10.1021/np0497301. View

14.

Carpenter J . State of the science: hot flashes and cancer. Part 2: management and future directions. Oncol Nurs Forum. 2005; 32(5):969-78. DOI: 10.1188/05.ONF.969-978. View

15.

Osmers R, Friede M, Liske E, Schnitker J, Freudenstein J, Henneicke-von Zepelin H . Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol. 2005; 105(5 Pt 1):1074-83. DOI: 10.1097/01.AOG.0000158865.98070.89. View

16.

BOLLE P, Mastrangelo S, Perrone F, Evandri M . Estrogen-like effect of a Cimicifuga racemosa extract sub-fraction as assessed by in vivo, ex vivo and in vitro assays. J Steroid Biochem Mol Biol. 2007; 107(3-5):262-9. DOI: 10.1016/j.jsbmb.2007.03.044. View

17.

Fabricant D, Nikolic D, Lankin D, Chen S, Jaki B, Krunic A . Cimipronidine, a cyclic guanidine alkaloid from Cimicifuga racemosa. J Nat Prod. 2005; 68(8):1266-70. DOI: 10.1021/np050066d. View

18.

Sugimoto Y, Yamada J, HORISAKA K . Activation of peripheral serotonin2 receptors induces hypothermia in mice. Life Sci. 1991; 48(5):419-23. DOI: 10.1016/0024-3205(91)90497-y. View

19.

Friesen J, Pauli G . Reciprocal symmetry plots as a representation of countercurrent chromatograms. Anal Chem. 2007; 79(6):2320-4. DOI: 10.1021/ac062007q. View

20.

McKenna D, Jones K, Humphrey S, Hughes K . Black cohosh: efficacy, safety, and use in clinical and preclinical applications. Altern Ther Health Med. 2001; 7(3):93-100. View