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Rheum Rhaponticum Root Extract Improves Vasomotor Menopausal Symptoms and Estrogen-Regulated Targets in Ovariectomized Rat Model

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Rheum Rhaponticum Root Extract Improves Vasomotor Menopausal Symptoms and Estrogen-Regulated Targets in Ovariectomized Rat Model International Journal of Molecular Sciences Article Rheum rhaponticum Root Extract Improves Vasomotor Menopausal Symptoms and Estrogen-Regulated Targets in Ovariectomized Rat Model Mickey Wilson 1,2, Veera Konda 3, Kathryn Heidt 1,4, Thirumurugan Rathinasabapathy 1,2, Anuradha Desai 3 and Slavko Komarnytsky 1,2,* 1 Plants for Human Health Institute, North Carolina Research Campus, North Carolina State University, 600 Laureate Way, Kannapolis, NC 28081, USA; [email protected] (M.W.); [email protected] (K.H.); [email protected] (T.R.) 2 Department of Food, Bioprocessing & Nutrition Sciences, North Carolina State University, 400 Dan Allen Drive, Raleigh, NC 27695, USA 3 Metagenics Inc., 9770 44th Ave NW, Gig Harbor, WA 98332, USA; [email protected] (V.K.); [email protected] (A.D.) 4 Department of Biology, Catawba College, 2300 W Innes Street, Salisbury, NC 28144, USA * Correspondence: [email protected]; Tel.: +1-704-250-5459 Abstract: Ovarian insufficiency and ovariectomy are characterized by deregulated heat loss mech- anisms. Unlike hormone therapy, ERr 731 (a standardized botanical extract of Siberian rhubarb Rheum rhaponticum L. high in rhaponticin) acts like a selective estrogen receptor modulator for ERβ receptors and may offer a higher degree of safety while maintaining the desired efficacy profile. In this study, we examined the relationship between oral administration of ERr 731 and the underlying components of skin vasomotion responses in an ovariectomized (OVX) rat model. ERr 731 dose- Citation: Wilson, M.; Konda, V.; ◦ dependently reduced tail skin temperature (Tskin) values by an average of 1 C. The rapid onset of Heidt, K.; Rathinasabapathy, T.; Desai, this effect was observed in 1 and 3 mg/kg/day ERr 731 groups as early as day 2 of administration, A.; Komarnytsky, S. Rheum rhaponticum Root Extract Improves and remained in place for the duration of the treatment (2 weeks). Substituting ERr 731 after E2 Vasomotor Menopausal Symptoms withdrawal helped maintain body temperature similarly to E2 alone, suggesting the usefulness of and Estrogen-Regulated Targets in ERr 731 for replacing existing hormonal therapy in humans. ERr 731 also acted as a highly selective Ovariectomized Rat Model. Int. J. agonist for ERβ in the hypothalamus of OVX rats, as well as in ERα/β cell-based reporter assays. Mol. Sci. 2021, 22, 1032. https:// These data validate the OVX/Tskin rat model as a suitable screening platform to evaluate botanical doi.org/10.3390/ijms22031032 and pharmaceutical treatments of menopause, while providing further evidence for the efficacy of ERr 731 towards alleviating vasomotor menopausal symptoms and improving wellbeing during the Academic Editor: Raffaele Capasso menopausal transition. Received: 15 December 2020 Accepted: 14 January 2021 Keywords: postmenopausal; estrogens; hot flashes; HRT; ERr 731 Published: 21 January 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. An estimated 6000 American women transition to menopause every day, with 75% of women aged 50 to 55 years old assumed to be postmenopausal [1]. Among the eleven key health issues selected in terms of burden exerted in women’s mortality, morbidity, disability and quality of life, vasomotor symptoms play a prominent role [2]. To date, the most effective and reliable therapy for menopausal vasomotor symptoms (e.g., hot Copyright: © 2021 by the authors. flushes, night sweats) is hormone replacement therapy (HRT). However, long-term HRT Licensee MDPI, Basel, Switzerland. This article is an open access article carries the increased risk of hormone-related cancers and cardiovascular disease [3]. Mood distributed under the terms and modulators and selective serotonin re-uptake inhibitors are commonly recommended for conditions of the Creative Commons short-term use in highly symptomatic women who are not HRT candidates, but these Attribution (CC BY) license (https:// treatments lack supported data on safety and efficacy [4]. Natural approaches for hot flush creativecommons.org/licenses/by/ relief aim to reduce the daily vasomotor symptoms (frequency, intensity, and number) and 4.0/). improve quality of life through supplementation with phytoestrogens (soy, red clover, flax, Int. J. Mol. Sci. 2021, 22, 1032. https://doi.org/10.3390/ijms22031032 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 13 for hot flush relief aim to reduce the daily vasomotor symptoms (frequency, intensity, and Int. J. Mol. Sci. 2021, 22, 1032 2 of 12 number) and improve quality of life through supplementation with phytoestrogens (soy, red clover, flax, hops, hesperidin, and kudzu) and non-phytoestrogens, i.e., black cohosh, essential fatty acids, vitamin E, and succinates [5]. Unlike HRT, these approaches may hops,specifically hesperidin, target andspecific kudzu) estrogen and non-phytoestrogens,receptors (ER) and therefore i.e., black offer cohosh, more essentialselective fattyclin- acids,ical benefits vitamin [6]. E, and succinates [5]. Unlike HRT, these approaches may specifically target specificRhapontic estrogen rhubarb receptors roots (ER) (Rheum and therefore rhaponticum offer L., more family selective Polygonaceae) clinical benefits contain [6 ].a sig- nificantRhapontic amount rhubarb of hydroxystilbene roots (Rheum compou rhaponticumnds L.,without family any Polygonaceae) anthraquinones contain [7]. a The sig- nificantstandardized amount ERr of 731 hydroxystilbene extract contains compounds rhaponticin without and desoxyrhaponticin any anthraquinones glycosides [7]. The as standardizedthe main bioactive ERr 731constituents extract contains (Figure rhaponticin1), in addition and to desoxyrhaponticinlesser amounts of their glycosides respective as therhapontigenin main bioactive and constituentsdesoxyrhapontigenin (Figure1), inaglycones addition (~5%) to lesser [8]. amountsThe ERr 731 of their extract, respective as well rhapontigeninas its individual and compounds, desoxyrhapontigenin have been demonstrated aglycones (~5%) to act [8 as]. potent, The ERr selective 731 extract, ERβ ag- as wellonists as in its human individual endometrial compounds, cells, have without been significant demonstrated ERα to effects act as [9]. potent, The selectivesafety of ER ERrβ agonists731 was inevaluated human endometrialin 90-day rat cells, [10] without and 13-week significant dog ER[11]α studies.effects [9 Subsequent]. The safety clinical of ERr 731investigations was evaluated suggested in 90-day that ratERr [10 731] and was 13-week well tolerated dog [11 in] studies.the long-term Subsequent observational clinical investigationsstudies [7,12]. ERr suggested 731 was that effective ERr 731 in wasdecrea wellsing tolerated the number in the and long-term severity observationalof hot flushes studiesin a 12-week [7,12]. multicenter ERr 731 was trial effective that included in decreasing 109 women the number with climacteric and severity complaints of hot flushes [7], a in a 12-week multicenter trial that included 109 women with climacteric complaints [7], a menopause rating scale total score given after 6 months of treatment in 252 women [13], menopause rating scale total score given after 6 months of treatment in 252 women [13], as as well as 112 perimenopausal women with menopausal symptoms followed for 12 weeks well as 112 perimenopausal women with menopausal symptoms followed for 12 weeks [14]. [14]. Postmarketing surveillance data from Germany (140 million daily doses), the United Postmarketing surveillance data from Germany (140 million daily doses), the United States States and Canada (13 million) suggest that the extract is generally safe for consumption and Canada (13 million) suggest that the extract is generally safe for consumption [15]. [15]. However, it is not clear how effective ERr 731 supplementation is following the sub- However, it is not clear how effective ERr 731 supplementation is following the substitution stitution after termination of HRT (E2 withdrawal). after termination of HRT (E2 withdrawal). Figure 1. Schematic representationrepresentation ofof bioactivebioactive constituents constituents from from the the ERr ERr 731 731 rhubarb rhubarb root root extract extract in comparisonin comparison to theirto their respective respective glycosides glycosides and and trans-resveratrol. trans-resveratrol. In rats,rats, vasodilationvasodilation of of the the tail tail is is a a primary primary heat-dissipating heat-dissipating mechanism mechanism [16 [16]] that that can can be monitoredbe monitored by measuringby measuring tail skintail skin temperature temperature Tskin T[17skin]. [17]. Tskin Tisskin increased is increased by ovariectomy by ovariec- (OVX)tomy (OVX) and reduced and reduced by administration by administration of 17 βof-estradiol 17β-estradiol (E2), (E thus2), thus making making the OVXthe OVX rat modelrat model combined combined with with an inexpensive,an inexpensive, non-invasive non-invasive Tskin Tskinmonitoring monitoring device device attached attached in ain protective a protective covering covering on on the the surface surface of of the the tail tail a a versatile versatile screening screening platform platform toto evaluateevaluate botanical and pharmaceutical treatments of hothot flushesflushes andand generalgeneral wellbeingwellbeing duringduring menopause [[18].18]. Because hot flushesflushes correlatecorrelate toto aa spikingspiking ofof thethe peripheral LHLH andand GnRHGnRH released fromfrom thethe hypothalamus,hypothalamus,
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