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The effects of Korean Red Ginseng on stress-related neurotransmitters and gene expression: A randomized, double-blind, placebo-controlled trial

  • Jihyun Yoon (Department of Family Medicine, Korea University Anam Hospital) ;
  • Byoungjin Park (Department of Family Medicine, Yonsei University College of Medicine) ;
  • Kyung-Won Hong (R&D Division, Theragen Health Co., Ltd) ;
  • Dong-Hyuk Jung (Department of Family Medicine, Yonsei University College of Medicine)
  • Received : 2023.03.06
  • Accepted : 2023.08.06
  • Published : 2023.11.01

Abstract

Background: Korean Red Ginseng (KRG) is an effective anti-stress treatment. In this study, we investigated the therapeutic potential effects of KRG on relieving stress in a general population using transcriptome analysis. Methods: We conducted an 8-week clinical pilot study on 90 healthy men who reported stress. The study was completed by 43 participants in the KRG group and 44 participants in the placebo group. Participants were randomized 1:1 to the KRG and placebo groups. We evaluated the stress by stress response inventory (SRI) at baseline and 8 weeks. The main outcomes were changes in the levels of neurotransmitters (NTs) and NT-related gene expression. NTs were analyzed using automated (GC) content, and levels of gene expression were measured by reads per kilobase of transcript per million mapped reads (RPKM). Results: The KRG group showed significantly preserved epinephrine decrease compared with placebo group at 8 weeks (changes in epinephrine, KRG vs. placebo; -1623.2 ± 46101.5 vs. -35116.3 ± 86288.2, p = 0012). Among subjects who higher SRI score, meaning stress increased compared to baseline, the KRG group showed a smaller decrease in serotonin than the placebo group (changes in serotonin, KRG vs. placebo; -2627.5 ± 5859.1 vs, -8087.4 ± 7162.4, p = 0.005) and a smaller increase in cortisol than the placebo group (changes in cortisol, KRG vs. placebo; 1912.7 ± 10097.75 vs. 8046.2 ± 8050.6 , p = 0.019) in subgroup analysis. Transcriptome findings indicated that KRG intake affects gene expression related with metabolism of choline, adrenalin, and monoamine. Conclusion: These findings suggest that KRG has beneficial effects on the amelioration of stress response in NTs, and this effect is more prominent in stressful situations. Further clinical studies are required to confirm the anti-stress effect of KRG.

Keywords

References

  1. Chrousos GP, Gold PW. The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis. JAMA 1992;267(9):1244-52. https://doi.org/10.1001/jama.1992.03480090092034
  2. Moore K, Lookingland K. Dopaminergic neuronal systems in the hypothalmus. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. New York: Raven Press; 2000.
  3. Kumar A, Rinwa P, Kaur G, Machawal L. Stress: neurobiology, consequences and management. J Pharm Bioallied Sci 2013;5(2):91.
  4. Dragano N, Siegrist J, Nyberg ST, Lunau T, Fransson EI, Alfredsson L, Bjorner JB, Borritz M, Burr H, Erbel R. Effortereward imbalance at work and incident coronary heart disease. Epidemiology 2017;28(4):619-26. https://doi.org/10.1097/EDE.0000000000000666
  5. Nyberg ST, Fransson EI, Heikkil€a K, Ahola K, Alfredsson L, Bjorner JB, Borritz M, Burr H, Dragano N, Goldberg M. Job strain as a risk factor for type 2 diabetes: a pooled analysis of 124,808 men and women. Diabetes Care 2014;37(8):2268-75. https://doi.org/10.2337/dc13-2936
  6. Russ TC, Stamatakis E, Hamer M, Starr JM, Kivim€aki M, Batty GD. Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies. BMJ 2012;345.
  7. Zhou Z, Zhu G, Hariri AR, Enoch M-A, Scott D, Sinha R, Virkkunen M, Mash DC, Lipsky RH, Hu X-Z. Genetic variation in human NPY expression affects stress response and emotion. Nature 2008;452(7190):997-1001. https://doi.org/10.1038/nature06858
  8. McEwen BS. Understanding the potency of stressful early life experiences on brain and body function. Metabolism 2008;57:S11-5. https://doi.org/10.1016/j.metabol.2008.07.006
  9. Yang T, Yang XY, Yu L, Cottrell RR, Jiang S. Individual and regional association between socioeconomic status and uncertainty stress, and life stress: a representative nationwide study of China. Int J Equity Health 2017;16(1):1-8. https://doi.org/10.1186/s12939-016-0499-1
  10. Park J-H, Cha H-Y, Seo J-J, Hong J-T, Han K, Oh K-W. Anxiolytic-like effects of ginseng in the elevated plus-maze model: comparison of red ginseng and sun ginseng. Prog. Neuropsychopharmacol. Biol.Psychiatry 2005;29(6):895-900. https://doi.org/10.1016/j.pnpbp.2005.04.016
  11. Kim E-H, Kim I-H, Lee M-J, Nguyen CT, Ha J-A, Lee S-C, Choi S, Choi K-T, Pyo S, Rhee D-K. Anti-oxidative stress effect of red ginseng in the brain is mediated by peptidyl arginine deiminase type IV (PADI4) repression via estrogen receptor (ER) β up-regulation. J Ethnopharmacol 2013;148(2):474-85. https://doi.org/10.1016/j.jep.2013.04.041
  12. 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.Psychiatry 2009;33(8):1417-24. https://doi.org/10.1016/j.pnpbp.2009.07.020
  13. 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(3):402-7. https://doi.org/10.1016/j.jgr.2018.03.001
  14. Hasin Y, Seldin M, Lusis A. Multi-omics approaches to disease. Genome Biol 2017;18(1):1-15. https://doi.org/10.1186/s13059-016-1139-1
  15. Blumenberg M. Transcriptome analysis. BoDeBooks on Demand; 2019.
  16. Causton HC, Ren B, Koh SS, Harbison CT, Kanin E, Jennings EG, Lee TI, True HL, Lander ES, Young RA. Remodeling of yeast genome expression in response to environmental changes. Cell Mol Life Sci 2001;12(2):323-37. https://doi.org/10.1091/mbc.12.2.323
  17. Koh KB, Park JK, Kim CH, Cho S. Development of the stress response inventory and its application in clinical practice. Psychosom Med 2001;63(4):668-78. https://doi.org/10.1097/00006842-200107000-00020
  18. Chang KL, Ho PC. Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics for comparison of caffeinated and decaffeinated coffee and its implications for Alzheimer's disease. PLoS One 2014;9(8): e104621. https://doi.org/10.1371/journal.pone.0104621
  19. Trapnell C, Pachter L, Salzberg SL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 2009;25(9):1105-11. https://doi.org/10.1093/bioinformatics/btp120
  20. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, Van Baren MJ, Salzberg SL, Wold BJ, Pachter L. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 2010;28(5):511-5. https://doi.org/10.1038/nbt.1621
  21. Trapnell C, Hendrickson DG, Sauvageau M, Goff L, Rinn JL, Pachter L. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol 2013;31(1):46-53. https://doi.org/10.1038/nbt.2450
  22. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 1995;57(1):289-300. https://doi.org/10.1111/j.2517-6161.1995.tb02031.x
  23. Jang S-J, Lim H-J, Lim D-Y. Inhibitory effects of total ginseng saponin on catecholamine secretion from the perfused adrenal medulla of SHRs. J Ginseng Res 2011;35(2):176.
  24. Choi JH, Lee MJ, Jang M, Kim H-J, Lee S, Lee SW, Kim YO, Cho I-H. 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(1):107-15. https://doi.org/10.1016/j.jgr.2017.04.012
  25. Jiang N, Zhang Y, Yao C, Huang H, Wang Q, Huang S, He Q, Liu X. Ginsenosides Rb1 attenuates chronic social defeat stress-induced depressive behavior via regulation of SIRT1-NLRP3/Nrf2 pathways. Front Nutr 2022;9:868833.
  26. Kim DH, Kim DW, Jung BH, Lee JH, Lee H, Hwang GS, Kang KS, Lee JW. Ginsenoside Rb2 suppresses the glutamate-mediated oxidative stress and neuronal cell death in HT22 cells. J Ginseng Res 2019;43(2):326-34. https://doi.org/10.1016/j.jgr.2018.12.002
  27. 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
  28. 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(6):2470-82. https://doi.org/10.1159/000492684
  29. Oh Y, Lim HW, Park KH, Huang YH, Yoon JY, Kim K, Lim CJ. Ginsenoside Rc protects against UVB-induced photooxidative damage in epidermal keratinocytes. Mol Med Rep 2017;16(3):2907-14. https://doi.org/10.3892/mmr.2017.6943
  30. Tafet GE, Toister-Achituv M, Shinitzky M. Enhancement of serotonin uptake by cortisol: a possible link between stress and depression. Cogn Affect Behav Neurosci 2001;1(1):96-104. https://doi.org/10.3758/CABN.1.1.96
  31. Martin AM, Young RL, Leong L, Rogers GB, Spencer NJ, Jessup CF, Keating DJ. The diverse metabolic roles of peripheral serotonin. Endocrinology 2017;158(5):1049-63. https://doi.org/10.1210/en.2016-1839
  32. Kim H-J, Park S-D, Lee RM, Lee B-H, Choi S-H, Hwang S-H, Rhim H, Kim H-C, Nah S-Y. Gintonin attenuates depressive-like behaviors associated with alcohol withdrawal in mice. J Affect Disord 2017;215:23-9. https://doi.org/10.1016/j.jad.2017.03.026
  33. Xiang H, Liu Y, Zhang B, Huang J, Li Y, Yang B, Huang Z, Xiang F, Zhang H. The antidepressant effects and mechanism of action of total saponins from the caudexes and leaves of Panax notoginseng in animal models of depression. Phytomedicine 2011;18(8-9):731-8. https://doi.org/10.1016/j.phymed.2010.11.014
  34. Reader BF, Jarrett BL, McKim DB, Wohleb ES, Godbout JP, Sheridan JF. Peripheral and central effects of repeated social defeat stress: monocyte trafficking, microglial activation, and anxiety. Neuroscience 2015;289:429-42. https://doi.org/10.1016/j.neuroscience.2015.01.001
  35. Lowrance SA, Ionadi A, McKay E, Douglas X, Johnson JD. Sympathetic nervous system contributes to enhanced corticosterone levels following chronic stress. Psychoneuroendocrinology 2016;68:163-70. https://doi.org/10.1016/j.psyneuen.2016.02.027
  36. Avitsur R, Stark JL, Sheridan JF. Social stress induces glucocorticoid resistance in subordinate animals. Horm Behav 2001;39(4):247-57. https://doi.org/10.1006/hbeh.2001.1653
  37. Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D, Ferstl R, von Eynatten M, Wendt T, Rudofsky G. A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci USA 2003;100(4):1920-5. https://doi.org/10.1073/pnas.0438019100
  38. Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev 2004;56(3):331-49. https://doi.org/10.1124/pr.56.3.1
  39. Fatemi S, Folsom T. Catechol-O-methyltransferase gene regulation in rat frontal cortex. Mol Psychiatry 2007;12(4):322-3. https://doi.org/10.1038/sj.mp.4001958
  40. Chen JA, Vijapura S, Papakostas GI, Parkin SR, Kim DJH, Cusin C, Baer L, Clain AJ, Fava M, Mischoulon D. Association between physician beliefs regarding assigned treatment and clinical response: re-analysis of data from the hypericum depression trial study group. Asian J Psychiatr 2015;13:23-9. https://doi.org/10.1016/j.ajp.2014.12.002
  41. McEwen BS. Protective and damaging effects of stress mediators. N Egnl J Med 1998;338(3):171-9. https://doi.org/10.1056/NEJM199801153380307
  42. Naka I, Hikami K, Nakayama K, Koga M, Nishida N, Kimura R, Furusawa T, Natsuhara K, Yamauchi T, Nakazawa M. A functional SNP upstream of the beta-2 adrenergic receptor gene (ADRB2) is associated with obesity in Oceanic populations. Int J Obes (Lond) 2013;37(9):1204-10. https://doi.org/10.1038/ijo.2012.206
  43. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human. Beta. 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994;33(32):9414-9. https://doi.org/10.1021/bi00198a006