Browse > Article
http://dx.doi.org/10.1016/j.jgr.2020.08.006

The effect of ginsenosides on depression in preclinical studies: A systematic review and meta-analysis  

Kim, Yunna (College of Korean Medicine, Kyung Hee University)
Cho, Seung-Hun (College of Korean Medicine, Kyung Hee University)
Publication Information
Journal of Ginseng Research / v.45, no.3, 2021 , pp. 420-432 More about this Journal
Abstract
Background: Many ginsenosides have been shown to be efficacious for major depressive disorder (MDD), which is a highly recurrent disorder, through several preclinical studies. We aimed to review the literature assessing the antidepressant effects of ginsenosides on MDD animal models, to establish systematic scientific evidence in a rigorous manner. Methods: We performed a systematic review on the antidepressant effects of ginsenoside evaluated in in vivo studies. We searched for preclinical trials from inception to July 2019 in electronic databases such as Pubmed and Embase. In vivo studies examining the effect of a single ginsenoside on animal models of primary depression were included. Items of each study were evaluated by two independent reviewers. A meta-analysis was conducted to assess behavioral changes induced by ginsenoside Rg1, which was the most studied ginsenoside. Data were pooled using the random-effects models. Results: A total of 517 studies were identified, and 23 studies were included in the final analysis. They reported on many ginsenosides with different antidepressant effects and biological mechanisms of action. Of the 12 included articles assessing ginsenoside Rg1, pooled results of forced swimming test from 9 articles (mean difference (MD): 20.50, 95% CI: 16.13-24.87), and sucrose preference test from 11 articles (MD: 28.29, 95% CI: 22.90-33.69) showed significant differences compared with vehicle treatment. The risk of bias of each study was moderate, but there was significant heterogeneity across studies. Conclusion: These estimates suggest that ginsenosides, including ginsenoside Rg1, reduces symptoms of depression, modulates underlying mechanisms, and can be a promising antidepressant.
Keywords
Depression; Ginsenosides; Ginsenoside Rg1; Antidepressive agents; Neuroinflammation;
Citations & Related Records
Times Cited By KSCI : 3  (Citation Analysis)
연도 인용수 순위
1 Ramos-Hryb AB, Bahor Z, McCann S, Sena E, MacLeod MR, Lino de Oliveira C. Protocol for a systematic review and meta-analysis of data from preclinical studies employing forced swimming test: an update. BMJ Open Sci 2019;3.
2 Mou Z, Huang Q, Chu SF, Zhang MJ, Hu JF, Chen NH, Zhang JT. Antidepressive effects of ginsenoside Rg1 via regulation of HPA and HPG axis. Biomed Pharmacother 2017;92:962-71.   DOI
3 Lee S, Rhee D-K. Effects of ginseng on stress-related depression, anxiety, and the hypothalamicepituitaryeadrenal axis. J Ginseng Res 2017;41:589-94.   DOI
4 Jiang B, Xiong Z, Yang J, Wang W, Wang Y, Hu ZL, Wang F, Chen JG. Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus. Br J Pharmacol 2012;166:1872-87.   DOI
5 Zhang H, Zhou Z, Chen Z, Zhong Z, Li Z. Ginsenoside Rg3 exerts anti-depressive effect on an NMDA-treated cell model and a chronic mild stress animal model. J Pharmacol Sci 2017;134:45-54.   DOI
6 Kang A, Xie T, Zhu D, Shan J, Di L, Zheng X. Suppressive effect of ginsenoside Rg3 against lipopolysaccharide-induced depression-like behavior and neuroinflammation in mice. J Agri Food Chem 2017;65:6861-9.   DOI
7 Duong QHT, Nguyen PTV, Nguyen HTT, Nguyen DM. Effects of ocotillol-type saponins majonoside-R1 and vina-ginsenoside-R2 on abrogating depression and neuronal oxidative stress in socially isolated depression mouse model. Int J Appl Res Nat Prod 2016;9:27-32.
8 Zheng X, Liang Y, Kang A, Ma SJ, Xing L, Zhou YY, Dai C, Xie H, Xie L, Wang GJ, et al. Peripheral immunomodulation with ginsenoside Rg1 ameliorates neuroinflammation-induced behavioral deficits in rats. Neuroscience 2014;256:210-22.   DOI
9 Fan C, Zhu X, Song Q, Wang P, Liu Z, Yu SY. MiR-134 modulates chronic stress-induced structural plasticity and depression-like behaviors via downregulation of Limk1/cofilin signaling in rats. Neuropharmacology 2018;131:364-76.   DOI
10 Wu H, Zhu C, Guo J. [Effect of ginsenoside Rg1 on behaviors and hippocampal amino acids in depressive-like rats]. Zhongguo Zhong Yao Za Zhi = Zhongguo Zhongyao Zazhi = China J Chin Materia Medica 2012;37:3117-21.
11 Choi JH, Lee MJ, Jang M, Kim H-J, Lee S, Lee SW, et al. Panax ginseng exerts antidepressant-like effects by suppressing neuroinflammatory response and upregulating nuclear factor erythroid 2 related factor 2 signaling in the amygdala. J Ginseng Res 2018;42:107-15. https://doi.org/10.1016/j.jgr.2017.04.012.   DOI
12 Wang J, Chen Y, Dai C, Shang Y, Xie J. Ginsenoside Rh2 alleviates tumorassociated depression in a mouse model of colorectal carcinoma. Am J Transl Res 2016;8:2189-95.
13 Zhu X, Gao R, Liu Z, Cheng Z, Qi Y, Fan C, Yu SY. Ginsenoside Rg1 reverses stress-induced depression-like behaviours and brain-derived neurotrophic factor expression within the prefrontal cortex. Eur J Neurosci 2016;44:1878-85.   DOI
14 Liu Z, Qi Y, Cheng Z, Zhu X, Fan C, Yu SY. The effects of ginsenoside Rg1 on chronic stress induced depression-like behaviors, BDNF expression and the phosphorylation of PKA and CREB in rats. Neuroscience 2016;322:358-69.   DOI
15 Fan C, Song Q, Wang P, Li Y, Yang M, Yu SY. Neuroprotective effects of ginsenoside-rg1 against depression-like behaviors via suppressing glial activation, synaptic deficits, and neuronal apoptosis in rats. Front Immunol 2018;9:2889.   DOI
16 Lee B, Shim I, Lee H, Hahm DH. Effect of ginsenoside re on depression- and anxiety-like behaviors and cognition memory deficit induced by repeated immobilization in rats. J Microbiol Biotechnol 2012;22:708-20.   DOI
17 Ren Y, Wang JL, Zhang X, Wang H, Ye Y, Song L, Wang YJ, Tu MJ, Wang WW, Yang L, et al. Antidepressant-like effects of ginsenoside Rg2 in a chronic mild stress model of depression. Brain Res Bullet 2017;134:211-9.   DOI
18 Huang Q, Chu SF, Zhang JT, Chen N-h. Effects of Ginsenoside Rg1 on anti-depression and synaptic ultrastructure. Chin Pharmacol Bull 2013;29:1124-7.   DOI
19 Zhou H, Zhang H, Cui J, Liu Y, Wu R, Xiang H. Protopanaxadiol saponins in the caudexes and leaves of panax notoginseng coul d be the main constituents that contribute to its antidepressant effects. Int J Pharm Pharmaceut Sci 2014;6:301-11.
20 Xia CY, Chu SF, Zhang S, Gao Y, Ren Q, Lou YX, Luo P, Tian MT, Wang ZQ, Du GH, et al. Ginsenoside Rg1 alleviates corticosterone-induced dysfunction of gap junctions in astrocytes. J Ethnopharmacol 2017;208:207-13.   DOI
21 You Z, Yao Q, Shen J, Gu Z, Xu H, Wu Z, Chen C, Li L. Antidepressant-like effects of ginsenoside Rg3 in mice via activation of the hippocampal BDNF signaling cascade. J Nat Med 2017;71:367-79.   DOI
22 Yao Y, Sang W, Yang X-s, Zhai M-j, Wang L-l, Qin P-y, Wu L, Zhou X-r, Wang L-j, Li J-y, et al. Antidepressant effects of ginsenosides from panax notoginseng. J Integr Agri 2012;11:483-8.   DOI
23 Chen L, Qi Z, Shao Z, Li S, Qi Y, Gao K, Liu SX, Li Z, Sun YS, Li PY. Study on antidepressant activity of pseudo-ginsenoside HQ on depression-like behavior in mice, vol. 24. Basel, Switzerland): Molecules; 2019.
24 Cui J, Jiang L, Xiang H. Ginsenoside Rb3 exerts antidepressant-like effects in several animal models. J Psychopharmacol 2012;26:697-713.   DOI
25 Planchez B, Surget A, Belzung C. Animal models of major depression: drawbacks and challenges. J Neural Transm (Vienna) 2019;126:1383-408.   DOI
26 Wang G-L, He Z-M, Zhu H-Y, Gao Y-G, Zhao Y, Yang H, Zhang L-X. Involvement of serotonergic, noradrenergic and dopaminergic systems in the antidepressant-like effect of ginsenoside Rb1, a major active ingredient of Panax ginseng CA Meyer. J Ethnopharmacol 2017;204:118-24.   DOI
27 Huang J, Huang XN, Zhang S, Yang DL, Wu Q, Deng J, Gao Y. Effect of total ginsenosides on the cell cycle of rat vascular smooth muscle cell proliferation induced by PDGF-BB. Chin Pharmacol Bullet 2010;26:787-91.
28 Song L, Xu M-B, Zhou X-L, Zhang D-p, Zhang S-l, Zheng G-q. A preclinical systematic review of ginsenoside-Rg1 in experimental Parkinson's disease. Oxid Med Cell Long 2017. 2017.
29 Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci 2013;14:609-25.   DOI
30 Scheggi S, De Montis MG, Gambarana C. Making sense of rodent models of anhedonia. Int J Neuropsychopharmacol 2018;21:1049-65.   DOI
31 Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatr 2007;64:327-37.   DOI
32 Nam H, Clinton S, Jackson N, Kerman I. Learned helplessness and social avoidance in the Wistar-Kyoto rat. Front Behav Neurosci 2014;8.
33 Hao K, Gong P, Sun SQ, Hao HP, Wang GJ, Dai Y, Liang Y, Xie L, Li FY. Beneficial estrogen-like effects of ginsenoside Rb1, an active component of Panax ginseng, on neural 5-HT disposition and behavioral tasks in ovariectomized mice. Eur J Pharmacol 2011;659:15-25.   DOI
34 Jin C, Wang ZZ, Zhou H, Lou YX, Chen J, Zuo W, Tian MT, Wang ZQ, Du GH, Kawahata I, et al. Ginsenoside Rg1-induced antidepressant effects involve the protection of astrocyte gap junctions within the prefrontal cortex. Progr Neuro-Psychopharmacol Biolog Psychiatr 2017;75:183-91.   DOI
35 James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, Abbastabar H, Abd-Allah F, Abdela J, Abdelalim A, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2013;2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet 2018;392:1789-858.   DOI
36 World Health Organization. The global burden of disease: 2004 update. World Health Organization; 2008.
37 Liu L, Luo Y, Zhang R, Guo J. Effects of ginsenosides on hypothalamicpituitary-adrenal function and brain-derived neurotrophic factor in rats exposed to chronic unpredictable mild stress. Zhongguo Zhongyao Zazhi 2011;36:1342-7.
38 Kim JH, Yi Y-S, Kim M-Y, Cho JY. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J Ginseng Res 2017;41:435-43.   DOI
39 Xu D, Wang C, Zhao W, Gao S, Cui Z. Antidepressant-like effects of ginsenoside Rg5 in mice: involving of hippocampus BDNF signaling pathway. Neurosci Lett 2017;645:97-105.   DOI
40 Yu SE, Mwesige B, Yi Y-S, Yoo BC. Ginsenosides: the need to move forward from bench to clinical trials. J Ginseng Res 2019;43:361-7.   DOI
41 Dang H, Chen Y, Liu X, Wang Q, Wang L, Jia W, Wang Y. Antidepressant effects of ginseng total saponins in the forced swimming test and chronic mild stress models of depression. Prog Neuropsychopharmacol Biol Psychiatr 2009;33:1417-24.   DOI
42 Read JR, Sharpe L, Modini M, Dear BF. Multimorbidity and depression: a systematic review and meta-analysis. J Affect Disord 2017;221:36-46.   DOI
43 Global data. Major depressive disorder - global drug forecast and market assessment to 2025. 2015.
44 Yamada N, Araki H, Yoshimura H. Identification of antidepressant-like ingredients in ginseng root (Panax ginseng C.A. Meyer) using a menopausal depressive-like state in female mice: participation of 5-HT2A receptors. Psychopharmacology (Berl) 2011;216:589-99.   DOI
45 Lee B, Kim H, Shim I, Lee H, Hahm D-H. Wild ginseng attenuates anxiety-and depression-like behaviors during morphine withdrawal. J Microbiol Biotechnol 2011;21:1088-96.   DOI
46 Macleod MR, O'Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 2004;35:1203-8.   DOI
47 Zhang QL, Li SY, Li P. Effects of ginsenoside-Rg2 on mechanical allodynia, heat hyperalgeia, depressive state of rats with chronic sciatic nerve constriction injury. Zhongguo Ying Yong Sheng Li Xue Za Zhi = Zhongguo Yingyong Shenglixue Zazhi = Chinese Journal of Applied Physiology 2019;35:228-31.
48 Jiang N, Zhang BY, Dong LM, Lv JW, Lu C, Wang Q, Fan LX, Zhang HX, Pan RL, Liu XM. Antidepressant effects of dammarane sapogenins in chronic unpredictable mild stress-induced depressive mice. Phytother Res 2018;32:1023-9.   DOI
49 Hill MN, Hellemans KGC, Verma P, Gorzalka BB, Weinberg J. Neurobiology of chronic mild stress: parallels to major depression. Neurosci Biobehav Rev 2012;36:2085-117.   DOI
50 Kim N-H, Kim K-Y, Jeong H-J, Kim H-M. Antidepressant-like effect of altered Korean red ginseng in mice. Behav Med 2011;37:42-6.   DOI
51 Li Y, Chen C, Li S, Jiang C. Ginsenoside Rf relieves mechanical hypersensitivity, depression-like behavior, and inflammatory reactions in chronic constriction injury rats. Phytother Res 2019;33:1095-103.   DOI
52 Kim Y, Lee H-Y, Choi Y-J, Cho S-H. Antidepressant effects of ginsenoside Rf on behavioral change in the glial degeneration model of depression by reversing glial loss. J Ginseng Res 2020;44:603-10. https://doi.org/10.1016/j.jgr.2019.08.005.   DOI
53 Wiklund IK, Mattsson LA, Lindgren R, Limoni C. Effects of a standardized ginseng extract on quality of life and physiological parameters in symptomatic postmenopausal women: a double-blind, placebo-controlled trial. Swedish Alternative Medicine Group. Int J Clin Pharmacol Res 1999;19:89-99.
54 Hultman R, Mague SD, Li Q, Katz BM, Michel N, Lin L, Wang J, David LK, Blount C, Chandy R, et al. Dysregulation of prefrontal cortex-mediated slow-evolving limbic dynamics drives stress-induced emotional pathology. Neuron 2016;91:439-52.   DOI
55 Sheng C, Peng W, Xia Z-a, Wang Y, Chen Z, Su N, et al. The impact of ginsenosides on cognitive deficits in experimental animal studies of Alzheimer's disease: a systematic review. BMC Compl Alter Med 2015;15:386. https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-015-0894-y.   DOI
56 Pelizza L, Ferrari A. Anhedonia in schizophrenia and major depression: state or trait? Ann Gen Psychiatry 2009;8:22.   DOI
57 Kang O-J, Kim J-S. Comparison of ginsenoside contents in different parts of Korean ginseng (panax ginseng C.A. Meyer). Prev Nutr Food Sci 2016;21:389-92.   DOI
58 Lee B, Sur B, Cho S-G, Yeom M, Shim I, Lee H, Hahm D-H. Ginsenoside Rb1 rescues anxiety-like responses in a rat model of post-traumatic stress disorder. J Nat Med 2016;70:133-44.   DOI
59 Lee KJ, Ji GE. The effect of fermented red ginseng on depression is mediated by lipids. Nutr Neurosci 2014;17:7-15.   DOI
60 Yu H, Fan C, Yang L, Yu S, Song Q, Wang P, Mao X. Ginsenoside Rg1 prevents chronic stress-induced depression-like behaviors and neuronal structural plasticity in rats. Cell Physiol Biochem 2018;48:2470-82.   DOI
61 Baek JH, Heo J-Y, Fava M, Mischoulon D, Choi KW, Na EJ, Cho H, Jeon HJ. Effect of Korean Red Ginseng in individuals exposed to high stress levels: a 6-week, double-blind, randomized, placebo-controlled trial. J Ginseng Res 2019;43:402-7.   DOI
62 Oh HA, Kim D-E, Choi HJ, Kim NJ, Kim D-H. Anti-stress effects of 20(S)-Protopanaxadiol and 20(S)-Protopanaxatriol in immobilized mice. Biolog Pharmaceut Bullet 2015;38:331-5.   DOI
63 Song W, Guo Y, Jiang S, Wei L, Liu Z, Wang X, Su Y. Antidepressant effects of the ginsenoside metabolite compound K, assessed by behavioral despair test and chronic unpredictable mild stress model. Neurochem Res 2018;43:1371-82.   DOI
64 Xu C, Teng J, Chen W, Ge Q, Yang Z, Yu C, Yang Z, Jia W. 20(S)-protopanaxadiol, an active ginseng metabolite, exhibits strong antidepressant-like effects in animal tests. Progr Neuro-Psychopharmacol Biolog Psychiatr 2010;34:1402-11.   DOI
65 Zhang H, Li Z, Zhou Z, Yang H, Zhong Z, Lou C. Antidepressant-like effects of ginsenosides: a comparison of ginsenoside Rb3 and its four deglycosylated derivatives, Rg3, Rh2, compound K, and 20(S)-protopanaxadiol in mice models of despair. Pharmacol Biochem Behav 2016;140:17-26.   DOI
66 Pourmohamadi K, Ahmadzadeh A, Latifi M. Investigating the effects of oral ginseng on the cancer-related fatigue and quality of life in patients with nonmetastatic cancer. Int J Hematol-Oncol Stem Cell Res 2018;12:312-6.
67 Kim MS, Lim HJ, Yang HJ, Lee MS, Shin BC, Ernst E. Ginseng for managing menopause symptoms: a systematic review of randomized clinical trials. J Ginseng Res 2013;37:30-6.   DOI