Planta Med 2013; 79(09): 753-760
DOI: 10.1055/s-0032-1328552
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Salvia officinalis for Hot Flushes: Towards Determination of Mechanism of Activity and Active Principles

Sinikka Rahte
1   Centre for Pharmacognosy and Phytotherapy, School of Pharmacy, University of London, London, United Kingdom
,
Richard Evans
2   Centre for Toxicology, School of Pharmacy, University of London, London, United Kingdom
3   Current address: Institute for the Environment, Brunel University, Uxbridge, United Kingdom
,
Philippe J. Eugster
4   School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Laurence Marcourt
4   School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Jean-Luc Wolfender
4   School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Andreas Kortenkamp
2   Centre for Toxicology, School of Pharmacy, University of London, London, United Kingdom
3   Current address: Institute for the Environment, Brunel University, Uxbridge, United Kingdom
,
Deniz Tasdemir
1   Centre for Pharmacognosy and Phytotherapy, School of Pharmacy, University of London, London, United Kingdom
5   Current address: School of Chemistry, National University of Ireland, Galway, Ireland
› Author Affiliations
Further Information

Publication History

received 21 December 2012
revised 03 April 2013

accepted 09 April 2013

Publication Date:
13 May 2013 (online)

Abstract

Herbal medicinal products are commonly used in alternative treatment of menopausal hot flushes. In a recent clinical study, Salvia officinalis tincture was found to reduce hot flush frequency and intensity. The aim of the current study was the investigation of the mechanism(s) responsible for the anti-hot flush activity of S. officinalis and determination of its active principle(s). The 66 % ethanolic tincture, as well as the n-hexane, CHCl3, and aqueous ethanolic subextracts obtained from the tincture were studied in vitro for two of the most relevant activities, estrogenicity and selective serotonin reuptake inhibition. Because of an increased risk of menopausal women to suffer from Alzheimerʼs disease, an in vitro acetylcholinesterase inhibition assay was also employed. No activity was observed in the selective serotonin reuptake inhibition or the acetylcholinesterase inhibition assays at the highest test concentrations. The tincture showed no estrogenic effects whereas the aqueous ethanolic subextract exhibited estrogenicity in the ERLUX assay with an EC50 value of 64 µg/mL. Estrogenic activity-guided fractionation of the aqueous ethanolic subextract by a combination of reverse-phase vacuum liquid chromatography and gel chromatography identified luteolin-7-O-glucuronide (EC50 129 µg/mL) as the active component of the vacuum liquid chromatography fraction 4 (EC50 69 µg/mL). Luteolin-7-O-glucoside was identified as the putative estrogenic principle of the most potent minor fraction (7.6.7.6, EC50 0.7 µg/mL) obtained from the initial vacuum liquid chromatography fraction 7 (EC50 3 µg/mL). This study suggests the involvement of common and ubiquitous estrogenic flavonoids in the anti-hot flush effect of Salvia officinalis, a safe and commonly used herbal medicinal product during the menopause.

Supporting Information

 
  • References

  • 1 NAMS. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010; 2: 242-255
  • 2 Carroll DG, Kelley KW. Use of antidepressants for management of hot flashes. Pharmacotherapy 2009; 11: 1357-1374
  • 3 Daly E, Gray A, Barlow D, McPherson K, Roche M, Vessey M. Measuring the impact of menopausal symptoms on quality of life. BMJ 1993; 6908: 836-840
  • 4 Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci 1990; 592: 52-86
  • 5 Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes 2005; 3: 47
  • 6 Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol 1999; 1: 66-70
  • 7 Kronenberg F. Menopausal hot flashes: a review of physiology and biosociocultural perspective on methods of assessment. J Nutr 2010; 7: 1380S-1385S
  • 8 Weiss G, Skurnick JH, Goldsmith LT, Santoro NF, Park SJ. Menopause and hypothalamic-pituitary sensitivity to estrogen. JAMA 2004; 24: 2991-2996
  • 9 MacLennan A, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progesteron therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004; (4) CD002978
  • 10 Diel P, Olff S, Schmidt S, Michna H. Molecular identification of potential selective estrogen receptor modulator (SERM) like properties of phytoestrogens in the human breast cancer cell line MCF-7. Planta Med 2001; 6: 510-514
  • 11 Harris DM, Besselink E, Henning SM, Go VL, Heber D. Phytoestrogens induce differential estrogen receptor alpha- or beta-mediated responses in transfected breast cancer cells. Exp Biol Med 2005; 8: 558-568
  • 12 Berendsen HH. The role of serotonin in hot flushes. Maturitas 2000; 3: 155-164
  • 13 Shanafelt TD, Barton DL, Adjei AA, Loprinzi CL. Pathophysiology and treatment of hot flashes. Mayo Clin Proc 2002; 11: 1207-1218
  • 14 Sturdee DW. The menopausal hot flush-anything new?. Maturitas 2008; 1: 42-49
  • 15 Berendsen HH, Broekkamp CL. Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice. Br J Pharmacol 1990; 3: 667-673
  • 16 Blakely RD, Ramamoorthy S, Qian Y, Schroeter S, Bradely CC. Regulation of antidepressant-sensitive serotonin transporters. In: Reith MEA, editor Neurotranmittertransporters: structure, function and regulation. Totowa: Humana Press, Inc.; 1997: 29-72
  • 17 Togel B, Greve B, Raulin C. Current therapeutic strategies for hyperhidrosis: a review. Eur J Dermatol 2002; 3: 219-223
  • 18 Bartram T. Bartram encyclopedia of herbal medicine. London: Grace Publishers; 1995
  • 19 Bommer S, Klein P, Suter A. First time proof of sageʼs tolerability and efficacy in menopausal women with hot flushes. Adv Ther 2011; 6: 490-500
  • 20 Merchenthaler I, Funkhouser JM, Carver JM, Lundeen SG, Ghosh K, Winneker RC. The effect of estrogens and antiestrogens in a rat model for hot flush. Maturitas 1998; 3: 307-316
  • 21 Sipe K, Leventhal L, Burroughs K, Cosmi S, Johnston GH, Deecher DC. Serotonin 2A receptors modulate tail-skin temperature in two rodent models of estrogen deficiency-related thermoregulatory dysfunction. Brain Res 2004; 2: 191-202
  • 22 Rodriguez GJ, Roman DL, White KJ, Nichols DE, Barker EL. Distinct recognition of substrates by the human and Drosophila serotonin transporters. J Pharmacol Exp Ther 2003; 1: 338-346
  • 23 Wilson VS, Bobseine K, Gray jr. LE. Development and characterization of a cell line that stably expresses an estrogen-responsive luciferase reporter for the detection of estrogen receptor agonist and antagonists. Toxicol Sci 2004; 1: 69-77
  • 24 Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A, Amaducci LA, Brayne C, Copeland JR, Dartigues JF, Kragh-Sorensen P, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A. Rates and risk factors for dementia and Alzheimerʼs disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology 1999; 1: 78-84
  • 25 Alberca R, Montes-Latorre E, Gil-Neciga E, Mir-Rivera P, Lozano-San Martín P. Alzheimerʼs disease and women. Rev Neurol 2002; 6: 571-579
  • 26 Nilsson S, Koehler KF, Gustafsson JA. Development of subtype-selective oestrogen receptor-based therapeutics. Nat Rev Drug Discov 2011; 10: 778-792
  • 27 Greenblatt HM, Guillou C, Guenard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL. The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design. J Am Chem Soc 2004; 47: 15405-15411
  • 28 Perry NS, Houghton PJ, Jenner P, Keith A, Perry EK. Salvia lavandulaefolia essential oil inhibits cholinesterase in vivo . Phytomedicine 2002; 1: 48-51
  • 29 Loizzo MR, Menichini F, Tundis R, Bonesi M, Conforti F, Nadjafi F, Statti GA, Frega NG. In vitro biological activity of Salvia leriifolia benth essential oil relevant to the treatment of Alzheimerʼs disease. J Oleo Sci 2009; 8: 443-446
  • 30 Ren Y, Houghton PJ, Hider RC, Howes MJ. Novel diterpenoid acetylcholinesterase inhibitors from Salvia miltiorrhiza . Planta Med 2004; 3: 201-204
  • 31 Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi AH, Khani M. Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimerʼs disease: a double blind, randomized and placebo-controlled trial. J Clin Pharm Ther 2003; 1: 53-59
  • 32 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63
  • 33 Rhee IK, van de Meent M, Ingkaninan K, Verpoorte R. Screening for acetylcholinesterase inhibitors from Amaryllidaceae using silica gel thin-layer chromatography in combination with bioactivity staining. J Chromatogr A 2001; 915: 217-223
  • 34 Rhee IK, van Rijn RM, Verpoorte R. Qualitative determination of false-positive effects in the acetylcholinesterase assay using thin layer chromatography. Phytochem Anal 2003; 3: 127-131
  • 35 Kivrak I, Duru ME, Öztürk M, Mercan N, Harmandar M, Topcu G. Antioxidant, anticholinesterase and antimicrobial constituents from the essential oil and ethanol extract of Salvia potentillifolia . Food Chem 2009; 2: 470-479
  • 36 Özgen U, Sevindik H, Kazaz C, Yigit D, Kandemir A, Secen H, Çaliş I. A new sulfated alpha-ionone glycoside from Sonchus erzincanicus Matthews . Molecules 2010; 4: 2593-2599
  • 37 Lu Y, Foo LY. Flavonoid and phenolic glycosides from Salvia officinalis . Phytochemistry 2000; 3: 263-267
  • 38 Duke JA. Handbook of medicinal herbs. 2nd. edition. Boca Ranton: CRC Press; 2002
  • 39 Paris RR, Moyse H. Précis de Matière Médicale Paris: Collection de précis de pharmacie. Paris: Masson et Cie; 1971
  • 40 Kroszcynski S, Bychowska M. Lʼaction oestrogéne de la sauge (Salvia officinalis). Soc Biol Varsovie 1939; 6: 570-572
  • 41 Perry NS, Houghton PJ, Sampson J, Theobald AE, Hart S, Lis-Balchin M, Hoult JR, Evans P, Jenner P, Milligan S, Perry EK. In-vitro activity of S. lavandulaefolia (Spanish sage) relevant to treatment of Alzheimerʼs disease. J Pharm Pharmacol 2001; 10: 1347-1356
  • 42 van der Woude H, Ter Veld MG, Jacobs N, van der Saag PT, Murk AJ, Rietjens IM. The stimulation of cell proliferation by quercetin is mediated by the estrogen receptor. Mol Nutr Food Res 2005; 8: 763-771
  • 43 Seo HS, DeNardo DG, Jacquot Y, Laios I, Vidal DS, Zambrana CR, Leclercq G, Brown PH. Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha. Breast Cancer Res Treat 2006; 2: 121-134
  • 44 Moutsatsou P. The spectrum of phytoestrogens in nature: our knowledge is expanding. Hormones 2007; 3: 173-193
  • 45 Innocenti G, Vegeto E, DallʼAcqua S, Ciana P, Giorgetti M, Agradi E, Sozzi A, Fico G, Tome F. In vitro estrogenic activity of Achillea millefolium L. Phytomedicine 2007; 14: 147-152
  • 46 Garritano S, Pinto B, Giachi I, Pistelli L, Reali D. Assessment of estrogenic activity of flavonoids from Mediterranean plants using an in vitro short-term test. Phytomedicine 2005; 12: 143-147
  • 47 Virgili F, Acconcia F, Ambra R, Rinna A, Totta P, Marino M. Nutritional flavonoids modulate estrogen receptor alpha signaling. IUBMB Life 2004; 3: 145-151
  • 48 Shimoi K, Okada H, Furugori M, Goda T, Takase S, Suzuki M, Hara Y, Yamamoto H, Kinae N. Intestinal absorption of luteolin and luteolin 7-O-beta-glucoside in rats and humans. FEBS Lett 1998; 3: 220-224
  • 49 Wittemer SM, Ploch M, Windeck T, Muller SC, Drewelow B, Derendorf H, Veit M. Bioavailability and pharmacokinetics of caffeoylquinic acids and flavonoids after oral administration of Artichoke leaf extracts in humans. Phytomedicine 2005; 12: 28-38
  • 50 OʼLeary KA, Day AJ, Needs PW, Mellon FA, OʼBrien NM, Williamson G. Metabolism of quercetin-7- and quercetin-3-glucuronides by an in vitro hepatic model: the role of human beta-glucuronidase, sulfotransferase, catechol-O-methyltransferase and multi-resistant protein 2 (MRP2) in flavonoid metabolism. Biochem Pharmacol 2003; 3: 479-491
  • 51 Sperker B, Murdter TE, Schick M, Eckhardt K, Bosslet K, Kroemer HK. Interindividual variability in expression and activity of human beta-glucuronidase in liver and kidney: consequences for drug metabolism. J Pharmacol Exp Ther 1997; 2: 914-920
  • 52 Perry N, Court G, Bidet N, Court J, Perry E. European herbs with cholinergic activities: Potential in dementia therapy. Int J Geriatr Psych 1996; 12: 1063-1069