Browse > Article
http://dx.doi.org/10.1016/j.jgr.2022.07.007

Anxiolytic effect of Korean Red Ginseng through upregulation of serotonin and GABA transmission and BDNF expression in immobilized mice  

Bui, Bich Phuong (College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul)
Nguyen, Phuong Linh (College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul)
Do, Ha Thi Thu (College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul)
Cho, Jungsook (College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul)
Publication Information
Journal of Ginseng Research / v.46, no.6, 2022 , pp. 819-829 More about this Journal
Abstract
Background: Anxiolytic properties of Korean Red Ginseng (KRG) have been previously reported. However, the exact mechanism(s) of action remains to be elucidated. The present study investigated the effect of KRG on immobilization-induced anxiety-like behaviors in mice and explored the involvement of the serotonin and GABA systems and BDNF in the anxiolytic action. Methods: Mice were orally administered with KRG (200 mg/kg/day) for 4 weeks and immobilized once daily for 2 h. p-Chlorophenylalanine (p-CPA) was intraperitoneally injected on day 22-28, and flumazenil or bicuculline was injected on day 25-28. After behavioral evaluations, brains were dissected for biochemical analyses. Results: KRG improved immobilization-induced anxiety-like behaviors in mice, as assessed by the elevated plus maze (EPM) and marble burying tests (MBT). The anxiolytic effect of KRG was comparable to that of fluoxetine, a reference drug clinically used for anxiety disorders. A serotonin synthesis inhibitor, p-CPA, blocked the effect of KRG in the EPM and MBT, indicating the requirement of serotonin synthesis for anxiolytic action. In addition, the anxiolytic effect of KRG was inhibited by bicuculline (a GABAA antagonist) in MBT, implying the involvement of GABA transmission. Western blotting analyses revealed that KRG upregulated the expression of tryptophan hydroxylase and GABAA receptor in the brain, which was blocked by p-CPA. Enhanced BDNF expression by KRG in the hippocampus was also indicated to mediate the anxiolytic action of KRG in immobilized mice. Conclusion: KRG exhibited the anxiolytic effect in immobilized mice by multiple mechanisms of action, involving enhanced serotonin and GABA transmissions and BDNF expression.
Keywords
anxiolytic effect; GABA transmission; immobilization-induced anxiety-like behaviors; Korean Red Ginseng; serotonin transmission;
Citations & Related Records
Times Cited By KSCI : 7  (Citation Analysis)
연도 인용수 순위
1 Bandelow B, Michaelis S. Epidemiology of anxiety disorders in the 21st century. Dialogues Clin Neurosci 2015;17:327-35.   DOI
2 Gottschalk MG, Domschke K. Genetics of generalized anxiety disorder and related traits. Dialogues Clin Neurosci 2017;19:159-68.   DOI
3 Xie X, Yang H, An JJ, Houtz J, Tan JW, Xu H, Liao GY, Xu ZX, Xu B. Activation of anxiogenic circuits instigates resistance to diet-induced obesity via increased energy expenditure. Cell Metab 2019;29:917-31.   DOI
4 Seibenhener ML, Wooten MC. Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp 2015:52434.
5 Thibaut F. Anxiety disorders: a review of current literature. Dialogues Clin Neurosci 2017;19:87-8.   DOI
6 Llado-Pelfort L, Santana N, Ghisi V, Artigas F, Celada P. 5-HT1A receptor ag- onists enhance pyramidal cell firing in prefrontal cortex through a preferential action on GABA interneurons. Cereb Cortex 2012;22:1487-97.   DOI
7 Zaletel I, Filipovic D, Puskas N. Hippocampal BDNF in physiological conditions and social isolation. Rev Neurosci 2017;28:675-92.   DOI
8 Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 2008;33:73-83.   DOI
9 Anthony TE, Dee N, Bernard A, Lerchner W, Heintz N, Anderson DJ. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 2014;156:522-36.   DOI
10 Xiang M, Jiang Y, Hu Z, Yang Y, Du X, Botchway BO, Fang M. Serotonin receptors 2A and 1A modulate anxiety-like behavior in post-traumatic stress disordered mice. Am J Transl Res 2019;11:2288-303.
11 Stein L, Belluzzi JD, Wise CD. Benzodiazepines: behavioral and neurochemical mechanisms. Am J Psychiatry 1977;134:665-9.   DOI
12 Viggiano A, Cacciola G, Widmer DA, Viggiano D. Anxiety as a neurodevelopmental disorder in a neuronal subpopulation: evidence from gene expression data. Psychiatry Res 2015;228:729-40.   DOI
13 Bandelow B, Michaelis S, Wedekind D. Treatment of anxiety disorders. Dialogues Clin Neurosci 2017;19:93-107.   DOI
14 Blanco C, Raza MS, Schneier FR, Liebowitz MR. The evidence-based pharmacological treatment of social anxiety disorder. Int J Neuropsychopharmacol 2003;6:427-42.   DOI
15 Celada P, Puig MV, Casanovas JM, Guillazo G, Artigas F. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABAA, and glutamate receptors. J Neurosci 2001;21:9917-29.   DOI
16 Brambilla P, Perez J, Barale F, Schettini G, Soares JC. GABAergic dysfunction in mood disorders. Mol Psychiatry 2003;8:721-37. 15.   DOI
17 Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003;54:70-5.   DOI
18 Zhu G, Sun X, Yang Y, Du Y, Lin Y, Xiang J, Zhou N. Reduction of BDNF results in GABAergic neuroplasticity dysfunction and contributes to late-life anxiety disorder. Behav Neurosci 2019;133:212-24.   DOI
19 Madhav TR, Pei Q, Zetterstrom TS. Serotonergic cells of the rat raphe nuclei express mRNA of tyrosine kinase B (trkB), the high-affinity receptor for brain derived neurotrophic factor (BDNF). Brain Res Mol Brain Res 2001;93:56-63.   DOI
20 Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996;16:2365-72.   DOI
21 Park JH, Cha HY, Seo JJ, Hong JT, Han K, Oh KW. Anxiolytic-like effects of ginseng in the elevated plus-maze model: comparison of red ginseng and sun ginseng. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:895-900.   DOI
22 Jeong HG, Ko YH, Oh SY, Han C, Kim T, Joe SH. Effect of Korean Red Ginseng as an adjuvant treatment for women with residual symptoms of major depression. Asia Pac Psychiatry 2015;7:330-6.   DOI
23 Kim Y, Cho SH. The effect of ginsenosides on depression in preclinical studies: a systematic review and meta-analysis. J Ginseng Res 2021;45:420-32.   DOI
24 Bhattacharya SK, Mitra SK. Anxiolytic activity of Panax ginseng roots: an experimental study. J Ethnopharmacol 1991;34:87-92.   DOI
25 Zhao Z, Kim YW, Wu Y, Zhang J, Lee JH, Li X, Cho IJ, Park SM, Jung DH, Yang CH, et al. Korean Red Ginseng attenuates anxiety-like behavior during ethanol withdrawal in rats. J Ginseng Res 2014;38:256-63.   DOI
26 Kim TW, Choi HJ, Kim NJ, Kim DH. Anxiolytic-like effects of ginsenosides Rg3 and Rh2 from red ginseng in the elevated plus-maze model. Planta Med 2009;75:836-9.   DOI
27 Mohler H. The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology 2012;62:42-53.   DOI
28 Graeff FG, Guimar~ aes FS, De Andrade TG, Deakin JF. Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav 1996;54:129-41.   DOI
29 Lader M. Benzodiazepine harm: how can it be reduced? Br J Clin Pharmacol 2014;77:295-301.   DOI
30 _ Zmudzka E, Salaciak K, Sapa J, Pytka K. Serotonin receptors in depression and anxiety: insights from animal studies. Life Sci 2018;210:106-24.   DOI
31 Wang GL, He ZM, Zhu HY, Gao YG, Zhao Y, Yang H, Zhang LX. Involvement of serotonergic, noradrenergic and dopaminergic systems in the antidepressantlike effect of ginsenoside Rb1, a major active ingredient of Panax ginseng. C.A. Meyer. J Ethnopharmacol. 2017;204:118-24.   DOI
32 Lee B, Sur B, Lee H, Oh S. Korean Red Ginseng prevents posttraumatic stress disorder-triggered depression-like behaviors in rats via activation of the serotonergic system. J Ginseng Res 2020;44:644-54.   DOI
33 Lim SW, Doh KC, Jin L, Jin J, Piao SG, Heo SB, Chung BH, Yang CW. Ginseng treatment attenuates autophagic cell death in chronic cyclosporine nephropathy. Nephrology (Carlton). 2014;19:490-9.   DOI
34 Lee MR, Begum S, Sung CK. Effect of red and black ginseng on cholinergic markers, presynaptic markers, and neurotrophins in the brain of aged mice. Food Sci Biotechnol 2017;26:1743-7.   DOI
35 Gonzales EL, Jang JH, Mabunga DF, Kim JW, Ko MJ, Cho KS, Bahn GH, Hong M, Ryu JH, Kim HJ, et al. Supplementation of Korean Red Ginseng improves behavior deviations in animal models of autism. Food Nutr Res 2016;60: 29245.   DOI
36 Abouhosseini Tabari M, Hajizadeh Moghaddam A, Maggi F, Benelli G. Anxiolytic and antidepressant activities of Pelargonium roseum essential oil on Swiss albino mice: possible involvement of serotonergic transmission. Phytother Res 2018;32:1014-22.   DOI
37 Dela Pena IJI, Kim HJ, Botanas CJ, de la Pe ~ na JB, Van Le TH, Nguyen MD, Park JH, ~ Cheong JH. The psychopharmacological activities of Vietnamese ginseng in mice: characterization of its psychomotor, sedative-hypnotic, antistress, anxiolytic, and cognitive effects. J Ginseng Res 2017;41:201-8.   DOI
38 Alonso-Castro AJ, Gasca-Martinez D, Cortez-Mendoza LV, Alba-Betancourt C, Ruiz-Padilla AJ, Zapata-Morales JR. Evaluation of the neuropharmacological effects of Gardenin A in mice. Drug Dev Res 2020;81:600-8.   DOI
39 Jung JM, Park SJ, Lee YW, Lee HE, Hong SI, Lew JH, Hong E, Shim JS, Cheong JH, Ryu JH. The effects of a standardized Acanthopanax koreanum extract on stress-induced behavioral alterations in mice. J Ethnopharmacol 2013;148: 826-34.   DOI
40 Oh HA, Kim DE, Choi HJ, Kim NJ, Kim DH. Anti-stress effects of 20(S)-protopanaxadiol and 20(S)-protopanaxatriol in immobilized mice. Biol Pharm Bull 2015;38:331-5.   DOI
41 Kraeuter AK, Guest PC, Sarnyai Z. The elevated plus maze test for measuring anxiety-like behavior in rodents. Methods Mol Biol 2019;1916:69-74.   DOI
42 Kedia S, Chattarji S. Marble burying as a test of the delayed anxiogenic effects of acute immobilisation stress in mice. J Neurosci Methods 2014;233:150-4.   DOI
43 Lee B, Sur B, Cho SG, Yeom M, Shim I, Lee H, Hahm DH. Ginsenoside Rb1 rescues anxiety-like responses in a rat model of post-traumatic stress disorder. J Nat Med 2016;70:133-44.   DOI
44 Bui BP, Oh Y, Lee H, Cho J. Inhibition of inflammatory mediators and cell migration by 1,2,3,4-tetrahydroquinoline derivatives in LPS-stimulated BV2 microglial cells via suppression of NF-kB and JNK pathway. Int Immunopharmacol 2020;80:106231.   DOI
45 Jeong Y, Bae HJ, Park K, Bae HJ, Yang X, Cho YJ, Jung SY, Jang DS, Ryu JH. 4- Methoxycinnamic acid attenuates schizophrenia-like behaviors induced by MK-801 in mice. J Ethnopharmacol 2022;285:114864.   DOI
46 He B, Chen P, Yang J, Yun Y, Zhang X, Yang R, Shen Z. Neuroprotective effect of 20(R)-ginsenoside Rg3 against transient focal cerebral ischemia in rats. Neurosci Lett 2012;526:106-11.   DOI
47 Pellow S, File SE. Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav 1986;24:525-9.   DOI
48 Domingues M, Casaril AM, Birmann PT, Bampi SR, Lourenco D, Vieira BM, Dapper LH, Lenard~ ao EJ, Sonego M, Collares T, et al. Effects of a selanylimidazopyridine on the acute restraint stress-induced depressive- and anxietylike behaviors and biological changes in mice. Behav Brain Res 2019;366: 96-107.   DOI
49 Miao Z, Wang Y, Sun Z. The relationships between stress, mental disorders, and epigenetic regulation of BDNF. Int J Mol Sci 2020:21.
50 Kim HJ, Kim P, Shin CY. A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system. J Ginseng Res 2013;37:8-29.   DOI
51 Lee KH, Bahk WM, Lee SJ, Pae CU. Effectiveness and tolerability of Korean Red Ginseng augmentation in major depressive disorder patients with difficult-totreat in routine practice. Clin Psychopharmacol Neurosci 2020;18:621-6.   DOI
52 Jin Y, Cui R, Zhao L, Fan J, Li B. Mechanisms of Panax ginseng action as an antidepressant. Cell Prolif 2019;52:e12696.   DOI
53 Lee S, Rhee DK. Effects of ginseng on stress-related depression, anxiety, and the hypothalamic-pituitary-adrenal axis. J Ginseng Res 2017;41:589-94.   DOI
54 Lee B, Sur B, Cho SG, Yeom M, Shim I, Lee H, Hahm DH. Ginsenoside Rb1 rescues anxiety-like responses in a rat model of post-traumatic stress disorder. J Nat Med 2016;70:133-44.   DOI
55 Bao HY, Zhang J, Yeo SJ, Myung C-S, Kim HM, Kim JM, Park JH, Cho J, Kang JS. Memory enhancing and neuroprotective effects of selected ginsenosides. Arch Pharm Res 2005;28:335.   DOI
56 Carr MN, Bekku N, Yoshimura H. Identification of anxiolytic ingredients in ginseng root using the elevated plus-maze test in mice. Eur J Pharmacol 2006;531:160-5.   DOI
57 Cha HY, Park JH, Hong JT, Yoo HS, Song S, Hwang BY, Eun JS, Oh KW. Anxiolytic-like effects of ginsenosides on the elevated plus-maze model in mice. Biol Pharm Bull 2005;28:1621-5.   DOI