Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Korean Red Ginseng reduces chronic social defeat stress-induced mood disorders via N-methyl-D-aspartate receptor modulation in mice

  • Lee, Bo-Ram (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Ju-Hyun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Ko, Yong-Hyun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Seo, Jee-Yeon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Hur, Kwang-Hyun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Kim, Young-Jung (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Kim, Seon-Kyung (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Kim, Seong-Eon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Seok-Yong (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Jang, Choon-Gon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
  • Received : 2019.03.28
  • Accepted : 2019.11.01
  • Published : 2021.03.01
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Abstract

Background: A chronic social defeat stress (CSDS) model has been proposed as relevant to stress-induced behavioral change in humans. In this study, we examined the effect of Korean Red Ginseng (KRG) on CSDS-induced mood disorders and protein expression in an animal model. Methods: To evaluate the effect of KRG on social defeat stress, test mice were exposed in the resident aggressor's home cage compartment for 14 days beginning 1 h after KRG treatment (10, 20, and 40 mg/kg, per oral (p.o.)). After the exposure, behavioral tests to measure anxiety, social interaction, and depression-like behavior were performed. To investigate the underlying mechanism, N-methyl-D-aspartate receptor expression levels in CSDS-induced mice were evaluated using Western blot analysis. Results: CSDS induced anxiety-like behaviors by decreasing central activity in the open-field test and open-arm approach in the elevated plus maze test and led to social avoidance behavior in the social interaction test. CSDS mice showed upregulated NR1, NR2A, and NR2B expression in the hippocampus. KRG 20 and 40 mg/kg ameliorated anxiety-like activities and KRG 20 mg/kg alleviated social avoidance by decreasing time in the corner zone. KRG treatment recovered CSDS-induced NR1, NR2A, and NR2B protein levels in the hippocampus. Conclusion: These results indicate that KRG has a therapeutic effect on CSDS-induced mood disorder by alleviating N-methyl-D-aspartate receptor overexpression in the hippocampus.

Keywords

Acknowledgement

This work was supported by the 2016 grant from the Korean Society of Ginseng with funding from the Korea Ginseng Corporation and by the Basic Science Research Program (No. 2012R1A5A2A28671860) through the National Research Foundation of Korea (NRF).

References

  1. Hammen C. Stress and depression. Annu Rev Clin Psychol 2005;1:293-319. https://doi.org/10.1146/annurev.clinpsy.1.102803.143938
  2. Tennant C. Life events, stress and depression: a review of recent findings. Aust N Z J Psychiatry 2002;36(2):173-82. https://doi.org/10.1046/j.1440-1614.2002.01007.x
  3. Litman L, Costantino G, Waxman R, Sanabria-Velez C, Rodriguez-Guzman VM, Lampon-Velez A, Brown R, Cruz T. Relationship between peer victimization and posttraumatic stress among primary school children. J Trauma Stress 2015;28(4):348-54. https://doi.org/10.1002/jts.22031
  4. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008;455(7215):894-902. https://doi.org/10.1038/nature07455
  5. Stefanski V. Social stress in laboratory rats: hormonal responses and immune cell distribution. Psychoneuroendocrinology 2000;25(4):389-406. https://doi.org/10.1016/S0306-4530(99)00066-9
  6. Fuchs E, Flugge G. Social stress in tree shrews: effects on physiology, brain function, and behavior of subordinate individuals. Pharmacol Biochem Behav 2002;73(1):247-58. https://doi.org/10.1016/S0091-3057(02)00795-5
  7. Rygula R, Abumaria N, Flugge G, Fuchs E, Ruther E, Havemann-Reinecke U. Anhedonia and motivational deficits in rats: impact of chronic social stress. Behav Brain Res 2005;162(1):127-34. https://doi.org/10.1016/j.bbr.2005.03.009
  8. Rygula R, Abumaria N, Domenici E, Hiemke C, Fuchs E. Effects of fluoxetine on behavioral deficits evoked by chronic social stress in rats. Behav Brain Res 2006;174(1):188-92. https://doi.org/10.1016/j.bbr.2006.07.017
  9. Huang GB, Zhao T, Muna SS, Bagalkot TR, Jin HM, Chae HJ, Chung YC. Effects of chronic social defeat stress on behaviour, endoplasmic reticulum proteins and choline acetyltransferase in adolescent mice. Int J Neuropsychopharmacol 2013;16(7):1635-47. https://doi.org/10.1017/S1461145713000060
  10. Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry 2003;54(3):338-52. https://doi.org/10.1016/S0006-3223(03)00347-0
  11. McEwen BS. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 2005;54(5 Suppl 1):20-3. https://doi.org/10.1016/j.metabol.2005.01.008
  12. McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci 1999;22:105-22. https://doi.org/10.1146/annurev.neuro.22.1.105
  13. Lowy MT, Gault L, Yamamoto BK. Adrenalectomy attenuates stress-induced elevations in extracellular glutamate concentrations in the hippocampus. J Neurochem 1993;61(5):1957-60. https://doi.org/10.1111/j.1471-4159.1993.tb09839.x
  14. Reznikov LR, Grillo CA, Piroli GG, Pasumarthi RK, Reagan LP, Fadel J. Acute stress-mediated increases in extracellular glutamate levels in the rat amygdala: differential effects of antidepressant treatment. Eur J Neurosci 2007;25(10):3109-14. https://doi.org/10.1111/j.1460-9568.2007.05560.x
  15. Bagley J, Moghaddam B. Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam. Neuroscience 1997;77(1):65-73. https://doi.org/10.1016/S0306-4522(96)00435-6
  16. Calabrese F, Guidotti G, Molteni R, Racagni G, Mancini M, Riva MA. Stress-induced changes of hippocampal NMDA receptors: modulation by duloxetine treatment. PLoS One 2012;7(5):e37916. https://doi.org/10.1371/journal.pone.0037916
  17. Fontella FU, Vendite DA, Tabajara AS, Porciuncula LO, da Silva Torres IL, Jardim FM, Martini L, Souza DO, Netto CA, Dalmaz C. Repeated restraint stress alters hippocampal glutamate uptake and release in the rat. Neurochem Res 2004;29(9):1703-9. https://doi.org/10.1023/B:NERE.0000035805.46592.6c
  18. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011;475(7354):91-5. https://doi.org/10.1038/nature10130
  19. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011;69(8):754-61. https://doi.org/10.1016/j.biopsych.2010.12.015
  20. Yang Y, Ju W, Zhang H, Sun L. Effect of ketamine on LTP and NMDAR EPSC in Hippocampus of the chronic social defeat stress mice model of depression. Front Behav Neurosci 2018;12:229. https://doi.org/10.3389/fnbeh.2018.00229
  21. Kutsuwada T, Kashiwabuchi N, Mori H, Sakimura K, Kushiya E, Araki K, Meguro H, Masaki H, Kumanishi T, Arakawa M, et al. Molecular diversity of the NMDA receptor channel. Nature 1992;358(6381):36-41. https://doi.org/10.1038/358036a0
  22. Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y, Delpire E, Hall BJ. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. Elife 2014;3:e03581. https://doi.org/10.7554/eLife.03581
  23. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 1995;269(5231):1737-40. https://doi.org/10.1126/science.7569905
  24. Cousins SL, Papadakis M, Rutter AR, Stephenson FA. Differential interaction of NMDA receptor subtypes with the post-synaptic density-95 family of membrane associated guanylate kinase proteins. J Neurochem 2008;104(4):903-13. https://doi.org/10.1111/j.1471-4159.2007.05067.x
  25. Sheng M. The postsynaptic NMDA-receptor-PSD-95 signaling complex in excitatory synapses of the brain. J Cell Sci 2001;114(Pt 7):1251. https://doi.org/10.1242/jcs.114.7.1251
  26. Calabrese F, Molteni R, Racagni G, Riva MA. Neuronal plasticity: a link between stress and mood disorders. Psychoneuroendocrinology 2009;34(Suppl 1):S208-16. https://doi.org/10.1016/j.psyneuen.2009.05.014
  27. McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry 2006;163(9):1531-41. quiz 666. https://doi.org/10.1176/appi.ajp.163.9.1531
  28. Lee YY, Park JS, Jung JS, Kim DH, Kim HS. Anti-inflammatory effect of ginsenoside Rg5 in lipopolysaccharide-stimulated BV2 microglial cells. Int J Mol Sci 2013;14(5):9820-33. https://doi.org/10.3390/ijms14059820
  29. Kim EH, Kim IH, Lee MJ, Thach Nguyen C, Ha JA, Lee SC, Choi S, Choi KT, Pyo S, Rhee DK. Anti-oxidative stress effect of red ginseng in the brain is mediated by peptidyl arginine deiminase type IV (PADI4) repression via estrogen receptor (ER) beta up-regulation. J Ethnopharmacol 2013;148(2):474-85. https://doi.org/10.1016/j.jep.2013.04.041
  30. 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 Agric Food Chem 2017;65(32):6861-9. https://doi.org/10.1021/acs.jafc.7b02386
  31. Baek JH, Heo JY, 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 2018.
  32. Golden SA, Covington 3rd HE, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc 2011;6(8):1183-91. https://doi.org/10.1038/nprot.2011.361
  33. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 2006;9(4):519-25. https://doi.org/10.1038/nn1659
  34. Lister RG. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berl) 1987;92(2):180-5. https://doi.org/10.1007/BF00177912
  35. Ko YH, Kwon SH, Hwang JY, Kim KI, Seo JY, Nguyen TL, Lee SY, Kim HC, Jang CG. The memory-enhancing effects of liquiritigenin by activation of NMDA receptors and the CREB signaling pathway in mice. Biomol Ther (Seoul) 2018;26(2):109-14. https://doi.org/10.4062/biomolther.2016.284
  36. Hollis F, Kabbaj M. Social defeat as an animal model for depression. ILAR Journal 2014;55(2):221-32. https://doi.org/10.1093/ilar/ilu002
  37. Iio W, Takagi H, Ogawa Y, Tsukahara T, Chohnan S, Toyoda A. Effects of chronic social defeat stress on peripheral leptin and its hypothalamic actions. BMC Neurosci 2014;15:72. https://doi.org/10.1186/1471-2202-15-72
  38. Iniguez SD, Riggs LM, Nieto SJ, Dayrit G, Zamora NN, Shawhan KL, Cruz B, Warren BL. Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice. Stress 2014;17(3):247-55. https://doi.org/10.3109/10253890.2014.910650
  39. Jeong JY, Lee DH, Kang SS. Effects of chronic restraint stress on body weight, food intake, and hypothalamic gene expressions in mice. Endocrinol Metab (Seoul) 2013;28(4):288-96. https://doi.org/10.3803/EnM.2013.28.4.288
  40. Jung YH, Hong SI, Ma SX, Hwang JY, Kim JS, Lee JH, Seo JY, Lee SY, Jang CG. Strain differences in the chronic mild stress animal model of depression and anxiety in mice. Biomolecules and Therapeutics 2014;22(5):453-9. https://doi.org/10.4062/biomolther.2014.058
  41. Pothion S, Bizot JC, Trovero F, Belzung C. Strain differences in sucrose preference and in the consequences of unpredictable chronic mild stress. Behav Brain Res 2004;155(1):135-46. https://doi.org/10.1016/j.bbr.2004.04.008
  42. Harris RB, Zhou J, Youngblood BD, Rybkin II, Smagin GN, Ryan DH. Effect of repeated stress on body weight and body composition of rats fed low- and high-fat diets. Am J Physiol 1998;275(6 Pt 2):R1928-38.
  43. Karu N, Reifen R, Kerem Z. Weight gain reduction in mice fed Panax ginseng saponin, a pancreatic lipase inhibitor. J Agric Food Chem 2007;55(8):2824-8. https://doi.org/10.1021/jf0628025
  44. Song YB, An YR, Kim SJ, Park HW, Jung JW, Kyung JS, Hwang SY, Kim YS. Lipid metabolic effect of Korean red ginseng extract in mice fed on a high-fat diet. J Sci Food Agric 2012;92(2):388-96. https://doi.org/10.1002/jsfa.4589
  45. Lee SH, Lee HJ, Lee YH, Lee BW, Cha BS, Kang ES, Ahn CW, Park JS, Kim HJ, Lee EY, et al. Korean red ginseng (Panax ginseng) improves insulin sensitivity in high fat fed Sprague-Dawley rats. Phytother Res 2012;26(1):142-7. https://doi.org/10.1002/ptr.3610
  46. Gorman JM. Comorbid depression and anxiety spectrum disorders. Depress Anxiety 1996;4(4):160-8. https://doi.org/10.1002/(SICI)1520-6394(1996)4:4<160::AID-DA2>3.0.CO;2-J
  47. Organization WH. International statistical classification of diseases and related health problems, tenth revision (ICD-10)1992.
  48. Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 2003;463(1-3):3-33. https://doi.org/10.1016/S0014-2999(03)01272-X
  49. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, Laplant Q, Graham A, Lutter M, Lagace DC, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 2007;131(2):391-404. https://doi.org/10.1016/j.cell.2007.09.018
  50. Kinsey SG, Bailey MT, Sheridan JF, Padgett DA, Avitsur R. Repeated social defeat causes increased anxiety-like behavior and alters splenocyte function in C57BL/6 and CD-1 mice. Brain Behav Immun 2007;21(4):458-66. https://doi.org/10.1016/j.bbi.2006.11.001
  51. Saul ML, Tylee D, Becoats KT, Guerrero BG, Sweeney P, Helmreich DL, Fudge JL. Long-term behavioral consequences of stress exposure in adolescent versus young adult rats. Behav Brain Res 2012;229(1):226-34. https://doi.org/10.1016/j.bbr.2012.01.022
  52. Strekalova T, Spanagel R, Bartsch D, Henn FA, Gass P. Stress-induced anhedonia in mice is associated with deficits in forced swimming and exploration. Neuropsychopharmacology 2004;29(11):2007-17. https://doi.org/10.1038/sj.npp.1300532
  53. Venzala E, Garcia-Garcia AL, Elizalde N, Delagrange P, Tordera RM. Chronic social defeat stress model: behavioral features, antidepressant action, and interaction with biological risk factors. Psychopharmacology (Berl) 2012a;224(2):313-25. https://doi.org/10.1007/s00213-012-2754-5
  54. Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 2006;311(5762):864-8. https://doi.org/10.1126/science.1120972
  55. Mayorga AJ, Lucki I. Limitations on the use of the C57BL/6 mouse in the tail suspension test. Psychopharmacology (Berl) 2001;155(1):110-2. https://doi.org/10.1007/s002130100687
  56. Miczek KA, Yap JJ, Covington HE. Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol Ther 2008;120(2):102-28. https://doi.org/10.1016/j.pharmthera.2008.07.006
  57. Kim M, Kim SO, Lee M, Park Y, Kim D, Cho KH, Kim SY, Lee EH. Effects of ginsenoside Rb1 on the stress-induced changes of BDNF and HSP70 expression in rat hippocampus. Environ Toxicol Pharmacol 2014;38(1):257-62. https://doi.org/10.1016/j.etap.2014.06.004
  58. Lee SH, Jung BH, Kim SY, Lee EH, Chung BC. The antistress effect of ginseng total saponin and ginsenoside Rg3 and Rb1 evaluated by brain polyamine level under immobilization stress. Pharmacol Res 2006;54(1):46-9. https://doi.org/10.1016/j.phrs.2006.02.001
  59. Xu JN, Chen LF, Su J, Liu ZL, Chen J, Lin QF, Mao WD, Shen D. The anxiolytic-like effects of ginsenoside Rg3 on chronic unpredictable stress in rats. Sci Rep 2018;8(1):7741. https://doi.org/10.1038/s41598-018-26146-5

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