Browse > Article
http://dx.doi.org/10.1016/j.jgr.2019.08.007

Korean Red Ginseng alleviates dehydroepiandrosterone-induced polycystic ovarian syndrome in rats via its antiinflammatory and antioxidant activities  

Choi, Jong Hee (Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University)
Jang, Minhee (Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University)
Kim, Eun-Jeong (Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University)
Lee, Min Jung (Department of Science in Korean Medicine and Brain Korea 21 Plus Program, Graduate School, Kyung Hee University)
Park, Kyoung Sun (Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation)
Kim, Seung-Hyun (College of Veterinary Medicine, Chonnam National University)
In, Jun-Gyo (Laboratory of Analysis R&D Headquarters, Korea Ginseng Corporation)
Kwak, Yi-Seong (Korea Ginseng Research Institute, Korea Ginseng Corporation)
Park, Dae-Hun (Department of Nursing, Dongshin University)
Cho, Seung-Sik (Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University)
Nah, Seung-Yeol (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University)
Cho, Ik-Hyun (Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University)
Bae, Chun-Sik (College of Veterinary Medicine, Chonnam National University)
Publication Information
Journal of Ginseng Research / v.44, no.6, 2020 , pp. 790-798 More about this Journal
Abstract
Background: Beneficial effects of Korean Red Ginseng (KRG) on polycystic ovarian syndrome (PCOS) remains unclear. Methods: We examined whether pretreatment (daily from 2 hours before PCOS induction) with KRG extract in water (KRGE; 75 and 150 mg/kg/day, p.o.) could exert a favorable effect in a dehydroepian-drosterone (DHEA)-induced PCOS rat model. Results: Pretreatment with KRGE significantly inhibited the elevation of body and ovary weights, the increase in number and size of ovarian cysts, and the elevation of serum testosterone and estradiol levels induced by DHEA. Pretreatment with KRGE also inhibited macrophage infiltration and enhanced mRNA expression levels of chemokines [interleukin (IL)-8, monocyte chemoattractant protein-1), proinflammatory cytokines (IL-1β, IL-6), and inducible nitric oxide synthase in ovaries induced by DHEA. It also prevented the reduction in mRNA expression of growth factors (epidermal growth factor, transforming growth factor-beta (EGF, TGF-β)) related to inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cell pathway and stimulation of the nuclear factor erythroid-derived 2-related factor 2 pathway. Interestingly, KRGE or representative ginsenosides (Rb1, Rg1, and Rg3(s)) inhibited the activity of inflammatory enzymes cyclooxygenase-2 and iNOS, cytosolic p-IκB, and nuclear p-nuclear factor kappa-light-chain-enhancer of activated B in lipopolysaccharide-induced RAW264.7 cells, whereas they increased nuclear factor erythroid-derived 2-related factor 2 nuclear translocation. Conclusion: These results provide that KRGE could prevent DHEA-induced PCOS via antiinflammatory and antioxidant activities. Thus, KRGE may be used in preventive and therapeutic strategies for PCOS-like symptoms.
Keywords
Dehydroepiandrosterone; Korean Red Ginseng extract; Polycystic ovarian syndrome;
Citations & Related Records
Times Cited By KSCI : 10  (Citation Analysis)
연도 인용수 순위
1 Li Y, Zheng Q, Sun D, Cui X, Chen S, Bulbul A, Liu S, Yan Q. Dehydroepiandrosterone stimulates inflammation and impairs ovarian functions of polycystic ovary syndrome. J Cell Physiol 2019;234:7435-47.   DOI
2 Jiang YC, Ma JX. The role of MiR-324-3p in polycystic ovary syndrome (PCOS) via targeting WNT2B. Eur Rev Med Pharmacol Sci 2018;22:3286-93.
3 Hashimoto R, Yu J, Koizumi H, Ouchi Y, Okabe T. Ginsenoside Rb1 prevents MPP(+)-Induced apoptosis in PC12 cells by stimulating estrogen receptors with consequent activation of ERK1/2, Akt and inhibition of SAPK/JNK, p38 MAPK. Evid Based Complement Alternat Med 2012;2012:693717.
4 Nguyen CT, Luong TT, Kim GL, Pyo S, Rhee DK. Korean Red Ginseng inhibits apoptosis in neuroblastoma cells via estrogen receptor beta-mediated phosphatidylinositol-3 kinase/Akt signaling. J Ginseng Res 2015;39:69-75.   DOI
5 Amato G, Conte M, Mazziotti G, Lalli E, Vitolo G, Tucker AT, Bellastella A, Carella C, Izzo A. Serum and follicular fluid cytokines in polycystic ovary syndrome during stimulated cycles. Obstet Gynecol 2003;101:1177-82.   DOI
6 Glintborg D, Andersen M, Richelsen B, Bruun JM. Plasma monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha are increased in patients with polycystic ovary syndrome (PCOS) and associated with adiposity, but unaffected by pioglitazone treatment. Clin Endocrinol (Oxf). 2009;71:652-8.   DOI
7 Hatzirodos N, Bayne RA, Irving-Rodgers HF, Hummitzsch K, Sabatier L, Lee S, Bonner W, Gibson MA, Rainey WE, Carr BR, et al. Linkage of regulators of TGFbeta activity in the fetal ovary to polycystic ovary syndrome. Faseb J 2011;25:2256-65.   DOI
8 Pisoschi AM, Pop A. The role of antioxidants in the chemistry of oxidative stress: a review. Eur J Med Chem 2015;97:55-74.   DOI
9 Murri M, Luque-Ramirez M, Insenser M, Ojeda-Ojeda M, Escobar-Morreale HF. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update 2013;19:268-88.   DOI
10 Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson's disease. Front Neuroanat 2015;9:91.
11 Du X, Xu H, Jiang H, Xie J. Akt/Nrf2 activated upregulation of heme oxygenase-1 involves in the role of Rg1 against ferrous iron-induced neurotoxicity in SKN-SH cells. Neurotox Res 2013;24:71-9.   DOI
12 Lee YY, Park JS, Lee EJ, Lee SY, Kim DH, Kang JL, Kim HS. Anti-inflammatory mechanism of ginseng saponin metabolite Rh3 in lipopolysaccharidestimulated microglia: critical role of 5'-adenosine monophosphate-activated protein kinase signaling pathway. J Agric Food Chem 2015;63:3472-80.   DOI
13 Chen XC, Zhu YG, Zhu LA, Huang C, Chen Y, Chen LM, Fang F, Zhou YC, Zhao CH. Ginsenoside Rg1 attenuates dopamine-induced apoptosis in PC12 cells by suppressing oxidative stress. Eur J Pharmacol 2003;473:1-7.   DOI
14 Nabavi SF, Sureda A, Habtemariam S, Nabavi SM. Ginsenoside Rd and ischemic stroke; a short review of literatures. J Ginseng Res 2015;39:299-303.   DOI
15 Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93.   DOI
16 He L, Ling L, Wei T, Wang Y, Xiong Z. Ginsenoside Rg1 improves fertility and reduces ovarian pathological damages in premature ovarian failure model of mice. Exp Biol Med (Maywood). 2017;242:683-91.   DOI
17 Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011;7:219-31.   DOI
18 Tan TQ, Ge C, Mi Y, Jin Y, Zhang C. Ginsenosides promote proliferation of granulosa cells from chicken prehierarchical follicles through PKC activation and up-regulated cyclin gene expression. Cell Biol Int 2010;34:769-75.   DOI
19 Tode T, Kikuchi Y, Hirata J, Kita T, Imaizumi E, Nagata I. [Inhibitory effects of oral administration of ginsenoside Rh2 on tumor growth in nude mice bearing serous cyst adenocarcinoma of the human ovary]. Nihon Sanka Fujinka Gakkai Zasshi 1993;45:1275-82.
20 Goodarzi MO, Louwers YV, Taylor KD, Jones MR, Cui J, Kwon S, Chen YD, Guo X, Stolk L, Uitterlinden AG, et al. Replication of association of a novel insulin receptor gene polymorphism with polycystic ovary syndrome. Fertil Steril 2011;95:1736-41. e1-11.   DOI
21 Norman RJ, Homan G, Moran L, Noakes M. Lifestyle choices, diet, and insulin sensitizers in polycystic ovary syndrome. Endocrine 2006;30:35-43.   DOI
22 Mulligan K, Yang Y, Wininger DA, Koletar SL, Parker RA, Alston-Smith BL, Schouten JT, Fielding RA, Basar MT, Grinspoon S. Effects of metformin and rosiglitazone in HIV-infected patients with hyperinsulinemia and elevated waist/hip ratio. AIDS 2007;21:47-57.   DOI
23 Taylor AE, McCourt B, Martin KA, Anderson EJ, Adams JM, Schoenfeld D, Hall JE. Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:2248-56.   DOI
24 Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, Crystal RG, Darnell RB, Ferrante RJ, Fillit H, et al. A call for transparent reporting to optimize the predictive value of preclinical research. Nature 2012;490:187-91.   DOI
25 Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997;3:359-65.   DOI
26 Kar S, Sanchita S. Clomiphene citrate,metformin or a combination of both as the first lineovulationinductiondrugfor AsianIndianwomenwithpolycysticovarian syndrome: a randomized controlled trial. J Hum Reprod Sci 2015;8:197-201.   DOI
27 Raja-Khan N, Stener-Victorin E, Wu X, Legro RS. The physiological basis of complementary and alternative medicines for polycystic ovary syndrome. Am J Physiol Endocrinol Metab 2011;301:E1-10.   DOI
28 Ding J, Xu Y, Ma X, An J, Yang X, Liu Z, Lin N. Estrogenic effect of the extract of Renshen (Radix Ginseng) on reproductive tissues in immature mice. J Tradit Chin Med 2015;35:460-7.   DOI
29 Kim EJ, Jang M, Choi JH, Park KS, Cho IH. An improved dehydroepiandrosterone-induced rat model of polycystic ovary syndrome (PCOS): post-pubertal improves PCOS's feature. Front Endocrinol (Lausanne) 2018 Dec 4;9:735.   DOI
30 Kim KH, Lee D, Lee HL, Kim CE, Jung K, Kang KS. Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative diseases: past findings and future directions. J Ginseng Res 2018;42:239-47.   DOI
31 Cho J, Park W, Lee S, Ahn W, Lee Y. Ginsenoside-Rb1 from Panax ginseng C.A. Meyer activates estrogen receptor-alpha and -beta, independent of ligand binding. J Clin Endocrinol Metab 2004;89:3510-5.   DOI
32 Wu J, Pan Z, Wang Z, Zhu W, Shen Y, Cui R, Lin J, Yu H, Wang Q, Qian J, et al. Ginsenoside Rg1 protection against beta-amyloid peptide-induced neuronal apoptosis via estrogen receptor alpha and glucocorticoid receptor-dependent anti-protein nitration pathway. Neuropharmacology 2012;63:349-61.   DOI
33 Xu Y, Ding J, Ma XP, Ma YH, Liu ZQ, Lin N. Treatment with Panax ginseng antagonizes the estrogen decline in ovariectomized mice. Int J Mol Sci 2014;15:7827-40.   DOI
34 Jung JH, Park HT, Kim T, Jeong MJ, Lim SC, Nah SY, Cho IH, Park SH, Kang SS, Moon CJ, et al. Therapeutic effect of Korean Red ginseng extract on infertility caused by polycystic ovaries. J Ginseng Res 2011;35:250-5.   DOI
35 Jang M, Lee MJ, Kim CS, Cho IH. Korean Red ginseng extract attenuates 3-nitropropionic acid-induced Huntington's-like symptoms. Evid Based Complement Alternat Med 2013;2013:237207.
36 Cho I. Effects of Panax ginseng in neurodegenerative diseases. J Ginseng Res 2012;36:342-53.   DOI
37 Jang M, Lee MJ, Lee JM, Bae CS, Kim SH, Ryu JH, Cho IH. Oriental medicine Kyung-Ok-Ko prevents and alleviates dehydroepiandrosterone-induced polycystic ovarian syndrome in rats. PLoS One 2014:9. e87623.   DOI
38 Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab 1999;84:1897-9.   DOI
39 Luchetti CG, Solano ME, Sander V, Arcos ML, Gonzalez C, Di Girolamo G, Chiocchio S, Cremaschi G, Motta AB. Effects of dehydroepiandrosterone on ovarian cystogenesis and immune function. J Reprod Immunol 2004;64:59-674.   DOI
40 Marcondes FK, Bianchi FJ, Tanno AP. Determination of the estrous cycle phases of rats: some helpful considerations. Braz J Biol 2002;62:609-14.   DOI
41 Choi JH, Jang M, Nah SY, Oh S, Cho IH. Multitarget effects of Korean Red Ginseng in animal model of Parkinson's disease: antiapoptosis, antioxidant, antiinflammation, and maintenance of blood-brain barrier integrity. J Ginseng Res 2018;42:379-88.   DOI
42 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using realtime quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402-8.   DOI
43 Solano ME, Sander VA, Ho H, Motta AB, Arck PC. Systemic inflammation, cellular influx and up-regulation of ovarian VCAM-1 expression in a mouse model of polycystic ovary syndrome (PCOS). J Reprod Immunol 2011;92:33-44.   DOI
44 Manneras L, Cajander S, Holmang A, Seleskovic Z, Lystig T, Lonn M, Stener-Victorin E. A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology 2007;148:3781-91.   DOI
45 Liu Q, Kou JP, Yu BY. Ginsenoside Rg1 protects against hydrogen peroxideinduced cell death in PC12 cells via inhibiting NF-kappaB activation. Neurochem Int 2011;58:119-25.   DOI
46 Maharjan R, Nagar PS, Nampoothiri L. Effect of Aloe barbadensis Mill. formulation on Letrozole induced polycystic ovarian syndrome rat model. J Ayurveda Integr Med 2011;1:273-9.   DOI
47 Bas D, Abramovich D, Hernandez F, Tesone M. Altered expression of Bcl-2 and Bax in follicles within dehydroepiandrosterone-induced polycystic ovaries in rats. Cell Biol Int 2011;35:423-9.   DOI
48 Benson S, Janssen OE, Hahn S, Tan S, Dietz T, Mann K, Pleger K, Schedlowski M, Arck PC, Elsenbruch S. Obesity, depression, and chronic low-grade inflammation in women with polycystic ovary syndrome. Brain Behav Immun 2008;22:177-84.   DOI
49 Wu R, Van der Hoek KH, Ryan NK, Norman RJ, Robker RL. Macrophage contributions to ovarian function. Hum Reprod Update 2004;10:119-33.   DOI
50 He B, Chen P, Yang J, Yun Y, Zhang X, Yang R, Shen Z. Neuroprotective effect of 20(R)-ginsenoside Rg(3) against transient focal cerebral ischemia in rats. Neurosci Lett 2012;526:106-11.   DOI
51 Izumo K, Horiuchi M, Komatsu M, Aoyama K, Bandow K, Matsuguchi T, Takeuchi M, Takeuchi T. Dehydroepiandrosterone increased oxidative stress in a human cell line during differentiation. Free Radic Res 2009;43:922-31.   DOI
52 Lee YM, Yoon H, Park HM, Song BC, Yeum KJ. Implications of red Panax ginseng in oxidative stress associated chronic diseases. J Ginseng Res 2017;41:113-9.   DOI
53 Elia E, Sander V, Luchetti CG, Solano ME, Di Girolamo G, Gonzalez C, Motta AB. The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice. Mol Hum Reprod 2006;12:475-81.   DOI
54 Hahn S, Janssen OE, Tan S, Pleger K, Mann K, Schedlowski M, Kimmig R, Benson S, Balamitsa E, Elsenbruch S. Clinical and psychological correlates of quality-of-life in polycystic ovary syndrome. Eur J Endocrinol 2005;153:853-60.   DOI
55 Zuo T, Zhu M, Xu W. Roles of oxidative stress in polycystic ovary syndrome and cancers. Oxid Med Cell Longev 2016;2016:8589318.
56 Sander V, Luchetti CG, Solano ME, Elia E, Di Girolamo G, Gonzalez C, Motta AB. Role of the N, N'-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone. Reproduction 2006;131:591-602.   DOI
57 Manneras L, Jonsdottir IH, Holmang A, Lonn M, Stener-Victorin E. Low-frequency electro-acupuncture and physical exercise improve metabolic disturbances and modulate gene expression in adipose tissue in rats with dihydrotestosterone-induced polycystic ovary syndrome. Endocrinology 2008;149:3559-68.   DOI
58 Ross R, Janssen I, Dawson J, Kungl AM, Kuk JL, Wong SL, Nguyen-Duy TB, Lee S, Kilpatrick K, Hudson R. Exercise-induced reduction in obesity and insulin resistance in women: a randomized controlled trial. Obes Res 2004;12:789-98.   DOI
59 Diamanti-Kandarakis E, Christakou C, Kandarakis H. Polycystic ovarian syndrome: the commonest cause of hyperandrogenemia in women as a risk factor for metabolic syndrome. Minerva Endocrinol 2007;32:35-47.
60 Johnson N. Metformin is a reasonable first-line treatment option for nonobese women with infertility related to anovulatory polycystic ovary syndrome-a meta-analysis of randomised trials. Aust N Z J Obstet Gynaecol 2011;51:125-9.   DOI