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Journal of Natural Medicines

, Volume 71, Issue 2, pp 367–379 | Cite as

Antidepressant-like effects of ginsenoside Rg3 in mice via activation of the hippocampal BDNF signaling cascade

  • Zhengchen YouEmail author
  • Qi Yao
  • Jianhong Shen
  • Zhikai Gu
  • Hui Xu
  • Zhonghua Wu
  • Chuanjun Chen
  • Luozhu Li
Original Paper

Abstract

Current antidepressants are clinically effective only after several weeks of administration. Ginsenoside Rg3 is one component of ginsenosides, with a similar chemical structure to ginsenoside Rg1. Here, we investigated the antidepressant effects of Rg3 in mouse models of depression. The antidepressant actions of Rg3 were first examined in the forced swim test (FST) and tail suspension test (TST), and then assessed in the chronic social defeat stress (CSDS) model of depression. The changes in the hippocampal brain-derived neurotrophic factor (BDNF) signaling pathway after CSDS and Rg3 treatment were investigated. A tryptophan hydroxylase inhibitor and a BDNF signaling inhibitor were also used to determine the pharmacological mechanisms of Rg3. It was found that Rg3 produced antidepressant effects in the FST and TST without affecting locomotor activity. Rg3 also prevented the CSDS-induced depressive-like symptoms. Moreover, Rg3 fully restored the CSDS-induced decrease in the hippocampal BDNF signaling pathway, and use of the BDNF signaling inhibitor blocked the antidepressant effects of Rg3. In conclusion, ginsenoside Rg3 has antidepressant effects via promotion of the hippocampal BDNF signaling pathway.

Keywords

Brain-derived neurotrophic factor Chronic social defeat stress Depression Ginsenoside Rg3 

Abbreviations

AMPK

AMP-activated protein kinase

ANOVA

Analysis of variance

BDNF

Brain-derived neurotrophic factor

CREB

cAMP response element-binding protein

CSDS

Chronic social defeat stress

FST

Forced swimming test

MAOI

Monoamine oxidase inhibitor

NARI

Noradrenergic reuptake inhibitor

PCPA

p-Chlorophenylalanine methyl ester

PI3K

Phosphoinositide 3-kinase

SNRI

Serotonin–noradrenaline reuptake inhibitor

SSRI

Selective serotonin reuptake inhibitor

TCA

Tricyclic antidepressant

TrkB

Tropomyosin receptor kinase B

TST

Tail suspension test

Notes

Acknowledgements

This work was funded by innovation and demonstration projects of Nantong Social Science and Technology (HS2011024) to Jianhong Shen.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to report.

References

  1. 1.
    Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S et al (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8–19CrossRefPubMedGoogle Scholar
  2. 2.
    Thase ME (2006) Preventing relapse and recurrence of depression: a brief review of therapeutic options. CNS Spectr 11:12–21CrossRefPubMedGoogle Scholar
  3. 3.
    McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA et al (2006) Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry 163:1531–1541 quiz 1666 CrossRefPubMedGoogle Scholar
  4. 4.
    Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861CrossRefPubMedGoogle Scholar
  5. 5.
    Lim JY, Park SI, Oh JH, Kim SM, Jeong CH, Jun JA et al (2008) Brain-derived neurotrophic factor stimulates the neural differentiation of human umbilical cord blood-derived mesenchymal stem cells and survival of differentiated cells through MAPK/ERK and PI3K/Akt-dependent signaling pathways. J Neurosci Res 86:2168–2178CrossRefPubMedGoogle Scholar
  6. 6.
    Castren E, Kojima M (2016) Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol Dis S0969–S9961(16):30169Google Scholar
  7. 7.
    Monteleone P, Serritella C, Martiadis V, Maj M (2008) Decreased levels of serum brain-derived neurotrophic factor in both depressed and euthymic patients with unipolar depression and in euthymic patients with bipolar I and II disorders. Bipolar Disord 10:95–100CrossRefPubMedGoogle Scholar
  8. 8.
    Duman RS (2004) Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromol Med 5:11–25CrossRefGoogle Scholar
  9. 9.
    Duman RS, Voleti B (2012) Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci 35:47–56CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Gass P, Riva MA (2007) CREB, neurogenesis and depression. BioEssays 29:957–961CrossRefPubMedGoogle Scholar
  12. 12.
    Blendy JA (2006) The role of CREB in depression and antidepressant treatment. Biol Psychiatry 59:1144–1150CrossRefPubMedGoogle Scholar
  13. 13.
    Leung KW, Wong AS (2010) Pharmacology of ginsenosides: a literature review. Chin Med 5:20CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lee YY, Park JS, Jung JS, Kim DH, Kim HS (2013) Anti-inflammatory effect of ginsenoside Rg5 in lipopolysaccharide-stimulated BV2 microglial cells. Int J Mol Sci 14:9820–9833CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhang Y, Zhang Z, Wang H, Cai N, Zhou S, Zhao Y et al (2016) Neuroprotective effect of ginsenoside Rg1 prevents cognitive impairment induced by isoflurane anesthesia in aged rats via antioxidant, anti-inflammatory and anti-apoptotic effects mediated by the PI3 K/AKT/GSK-3beta pathway. Mol Med Rep 14:2778–2784PubMedGoogle Scholar
  16. 16.
    Chen J, Wang Q, Wu H, Liu K, Wu Y, Chang Y et al (2016) The ginsenoside metabolite compound K exerts its anti-inflammatory activity by downregulating memory B cell in adjuvant-induced arthritis. Pharm Biol 54:1280–1288CrossRefPubMedGoogle Scholar
  17. 17.
    Dong X, Zheng L, Lu S, Yang Y (2015) Neuroprotective effects of pretreatment of ginsenoside Rb1 on severe cerebral ischemia-induced injuries in aged mice: involvement of anti-oxidant signaling. Geriatr Gerontol Int. doi: 10.1111/ggi.12699 Google Scholar
  18. 18.
    Chen Y, Xu Y, Zhu Y, Li X (2013) Anti-cancer effects of ginsenoside compound k on pediatric acute myeloid leukemia cells. Cancer cell Int 13:24CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jiang B, Xiong Z, Yang J, Wang W, Wang Y, Hu ZL et al (2012) Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus. Br J Pharmacol 166:1872–1887CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kim JH, Cho SY, Lee JH, Jeong SM, Yoon IS, Lee BH et al (2007) Neuroprotective effects of ginsenoside Rg3 against homocysteine-induced excitotoxicity in rat hippocampus. Brain Res 1136:190–199CrossRefPubMedGoogle Scholar
  21. 21.
    Tian J, Fu F, Geng M, Jiang Y, Yang J, Jiang W et al (2005) Neuroprotective effect of 20(S)-ginsenoside Rg3 on cerebral ischemia in rats. Neurosci Lett 374:92–97CrossRefPubMedGoogle Scholar
  22. 22.
    Kim J, Shim J, Lee S, Cho WH, Hong E, Lee JH et al (2016) Rg3-enriched ginseng extract ameliorates scopolamine-induced learning deficits in mice. BMC Complement Altern Med 16:66CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kim TW, Choi HJ, Kim NJ, Kim DH (2009) Anxiolytic-like effects of ginsenosides Rg3 and Rh2 from red ginseng in the elevated plus-maze model. Planta Med 75:836–839CrossRefPubMedGoogle Scholar
  24. 24.
    Ahn EJ, Choi GJ, Kang H, Baek CW, Jung YH, Woo YC et al (2016) Antinociceptive effects of ginsenoside Rg3 in a rat model of incisional pain. European surgical research. Eur Surg Res 57:211–223CrossRefPubMedGoogle Scholar
  25. 25.
    Jiang B, Huang C, Chen XF, Tong LJ, Zhang W (2015) Tetramethylpyrazine produces antidepressant-like effects in mice through promotion of BDNF signaling pathway. Int J Neuropsychopharmcol 18 (pii:pw010) Google Scholar
  26. 26.
    Jiang B, Huang C, Zhu Q, Tong LJ, Zhang W (2015) WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway. Psychopharmacology 232:1629–1642CrossRefPubMedGoogle Scholar
  27. 27.
    He B, Chen P, Yang J, Yun Y, Zhang X, Yang R et al (2012) Neuroprotective effect of 20(R)-ginsenoside Rg(3) against transient focal cerebral ischemia in rats. Neurosci Lett 526:106–111CrossRefPubMedGoogle Scholar
  28. 28.
    Braun A, Lommatzsch M, Neuhaus-Steinmetz U, Quarcoo D, Glaab T, McGregor GP et al (2004) Brain-derived neurotrophic factor (BDNF) contributes to neuronal dysfunction in a model of allergic airway inflammation. Br J Pharmacol 141:431–440CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A et al (2005) Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 25:281–290CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zhu XH, Yan HC, Zhang J, Qu HD, Qiu XS, Chen L et al (2010) Intermittent hypoxia promotes hippocampal neurogenesis and produces antidepressant-like effects in adult rats. J Neurosci 30:12653–12663CrossRefPubMedGoogle Scholar
  31. 31.
    Shichinohe H, Ishihara T, Takahashi K, Tanaka Y, Miyamoto M, Yamauchi T et al (2015) Bone marrow stromal cells rescue ischemic brain by trophic effects and phenotypic change toward neural cells. Neurorehabil Neural Repair 29:80–89CrossRefPubMedGoogle Scholar
  32. 32.
    Kleinridders A, Schenten D, Könner AC, Belgardt BF, Mauer J, Okamura T et al (2009) MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10:249–259CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336PubMedGoogle Scholar
  34. 34.
    Jiang B, Wang F, Yang S, Fang P, Deng ZF, Xiao JL et al (2015) SKF83959 produces antidepressant effects in a chronic social defeat stress model of depression through BDNF-TrkB pathway. Int J Neuropsychopharmacol 18 (pii:pyu096) Google Scholar
  35. 35.
    Jiang B, Song L, Wang CN, Zhang W, Huang C, Tong LJ (2016) Antidepressant-Like Effects of GM1 Ganglioside Involving the BDNF Signaling Cascade in Mice. Int J Neuropsychopharmacol 19 (pii:pyw046) Google Scholar
  36. 36.
    Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370CrossRefPubMedGoogle Scholar
  37. 37.
    Sarkisyan G, Roberts AJ, Hedlund PB (2010) The 5-HT(7) receptor as a mediator and modulator of antidepressant-like behavior. Behav Brain Res 209:99–108CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Jiang B, Wang W, Wang F, Hu ZL, Xiao JL, Yang S et al (2013) The stability of NR2B in the nucleus accumbens controls behavioral and synaptic adaptations to chronic stress. Biol Psychiatry 74:145–155CrossRefPubMedGoogle Scholar
  39. 39.
    Yao W, Gu C, Shao H, Meng G, Wang H, Jing X et al (2015) Tetrahydroxystilbene glucoside improves TNF-alpha-induced endothelial dysfunction: involvement of TGFbeta/Smad pathway and inhibition of vimentin expression. Am J Chin Med 43:183–198CrossRefPubMedGoogle Scholar
  40. 40.
    Meng G, Yang S, Chen Y, Yao W, Zhu H, Zhang W (2015) Attenuating effects of dihydromyricetin on angiotensin II-induced rat cardiomyocyte hypertrophy related to antioxidative activity in a NO-dependent manner. Pharm Biol 53:904–912CrossRefPubMedGoogle Scholar
  41. 41.
    Xu X, He M, Liu T, Zeng Y, Zhang W (2015) Effect of salusin-beta on peroxisome proliferator-activated receptor gamma gene expression in vascular smooth muscle cells and its possible mechanism. Cell Physiol Biochem 36:2466–2479CrossRefPubMedGoogle Scholar
  42. 42.
    Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790CrossRefPubMedGoogle Scholar
  43. 43.
    Cryan JF, Slattery DA (2007) Animal models of mood disorders: recent developments. Curr Opin Psychiatry 20:1–7CrossRefPubMedGoogle Scholar
  44. 44.
    Bourin M, Fiocco AJ, Clenet F (2001) How valuable are animal models in defining antidepressant activity? Hum Psychopharmacol 16:9–21CrossRefPubMedGoogle Scholar
  45. 45.
    Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ et al (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868CrossRefPubMedGoogle Scholar
  46. 46.
    Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525CrossRefPubMedGoogle Scholar
  47. 47.
    Barth M, Kriston L, Klostermann S, Barbui C, Cipriani A, Linde K (2016) Efficacy of selective serotonin reuptake inhibitors and adverse events: meta-regression and mediation analysis of placebo-controlled trials. Br J Psychiatry 208:114–119CrossRefPubMedGoogle Scholar
  48. 48.
    Coryell MW, Wunsch AM, Haenfler JM, Allen JE, Schnizler M, Ziemann AE et al (2009) Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior. J Neurosci 29:5381–5388CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597–606CrossRefPubMedGoogle Scholar
  50. 50.
    Altar CA (1999) Neurotrophins and depression. Trends Pharmacol Sci 20:59–61CrossRefPubMedGoogle Scholar
  51. 51.
    Castren E, Rantamaki T (2008) Neurotrophins in depression and antidepressant effects. Novartis Found Symp 289:43–52 discussion 53-49, 87-93 CrossRefPubMedGoogle Scholar
  52. 52.
    Lee S, Lee MS, Kim CT, Kim IH, Kim Y (2012) Ginsenoside Rg3 reduces lipid accumulation with AMP-activated protein kinase (AMPK) activation in HepG2 cells. Int J Mol Sci 13:5729–5739CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Hien TT, Kim ND, Pokharel YR, Oh SJ, Lee MY, Kang KW (2010) Ginsenoside Rg3 increases nitric oxide production via increases in phosphorylation and expression of endothelial nitric oxide synthase: essential roles of estrogen receptor-dependent PI3-kinase and AMP-activated protein kinase. Toxicol Appl Pharmacol 246:171–183CrossRefPubMedGoogle Scholar
  54. 54.
    Hwang JT, Lee MS, Kim HJ, Sung MJ, Kim HY, Kim MS et al (2009) Antiobesity effect of ginsenoside Rg3 involves the AMPK and PPAR-gamma signal pathways. Phytother Res 23:262–266CrossRefPubMedGoogle Scholar
  55. 55.
    Park MW, Ha J, Chung SH (2008) 20(S)-ginsenoside Rg3 enhances glucose-stimulated insulin secretion and activates AMPK. Biol Pharm Bull 31:748–751CrossRefPubMedGoogle Scholar
  56. 56.
    Kim DM, Leem YH (2016) Chronic stress-induced memory deficits are reversed by regular exercise via AMPK-mediated BDNF induction. Neuroscience 324:271–285CrossRefPubMedGoogle Scholar
  57. 57.
    Ghadernezhad N, Khalaj L, Pazoki-Toroudi H, Mirmasoumi M, Ashabi G (2016) Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway. Pharm Biol 54:2211–2219CrossRefPubMedGoogle Scholar
  58. 58.
    Yoon H, Oh YT, Lee JY, Choi JH, Lee JH, Baik HH et al (2008) Activation of AMP-activated protein kinase by kainic acid mediates brain-derived neurotrophic factor expression through a NF-kappaB dependent mechanism in C6 glioma cells. Biochem Biophys Res Commun 371:495–500CrossRefPubMedGoogle Scholar
  59. 59.
    Lee B, Sur B, Park J, Kim SH, Kwon S, Yeom M et al (2013) Ginsenoside rg3 alleviates lipopolysaccharide-induced learning and memory impairments by anti-inflammatory activity in rats. Biomol Ther (Seoul) 21:381–390CrossRefGoogle Scholar
  60. 60.
    Chen SD, Wang YL, Liang SF, Shaw FZ (2016) Rapid amygdala kindling causes motor seizure and comorbidity of anxiety- and depression-like behaviors in rats. Front Behav Neurosci 10:129PubMedPubMedCentralGoogle Scholar
  61. 61.
    Wang J, Jiang C, Chen L, Wu S, Lin J, Gao L et al (2016) A cross-sectional study to investigate the correlation between depression comorbid with anxiety and serum lipid levels. Compr Psychiatry 69:163–168CrossRefPubMedGoogle Scholar
  62. 62.
    Wu S, Gao Q, Zhao P, Gao Y, Xi Y, Wang X et al (2016) Sulforaphane produces antidepressant- and anxiolytic-like effects in adult mice. Behav Brain Res 301:55–62CrossRefPubMedGoogle Scholar
  63. 63.
    Caccamo A, Maldonado MA, Bokov AF, Majumder S, Oddo S (2010) CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 107:22687–22692CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Karamohamed S, Latourelle JC, Racette BA, Perlmutter JS, Wooten GF, Lew M et al (2005) BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study. Neurology 65:1823–1825CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan 2016

Authors and Affiliations

  • Zhengchen You
    • 1
    Email author
  • Qi Yao
    • 2
  • Jianhong Shen
    • 2
  • Zhikai Gu
    • 2
  • Hui Xu
    • 3
  • Zhonghua Wu
    • 3
  • Chuanjun Chen
    • 1
  • Luozhu Li
    • 1
  1. 1.Department of Burns and Plastic Surgery, Taizhou People’s HospitalThe Fifth Affiliated Hospital of Medical College of Nantong UniversityTaizhouChina
  2. 2.Department of NeurosurgeryAffiliated Hospital of Nantong UniversityNantongChina
  3. 3.Department of NeurosurgeryThe Sixth People’s Hospital of NantongNantongChina

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