Ginsenoside Rg1 Prevents Chemotherapy-Induced Cognitive Impairment: Associations with Microglia-Mediated Cytokines, Neuroinflammation, and Neuroplasticity

  • Dong-Dong Shi
  • Yu-Hua Huang
  • Cora Sau Wan Lai
  • Celia M. Dong
  • Leon C. Ho
  • Xiao-Yang Li
  • Ed X. Wu
  • Qi Li
  • Xiao-Min Wang
  • Yong-Jun Chen
  • Sookja Kim Chung
  • Zhang-Jin ZhangEmail author


Chemotherapy-induced cognitive impairment, also known as “chemobrain,” is a common side effect. The purpose of this study was to examine whether ginsenoside Rg1, a ginseng-derived compound, could prevent chemobrain and its underlying mechanisms. A mouse model of chemobrain was developed with three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination at a 2-day interval. Rg1 (5 and 10 mg/kg daily) was given 1 week prior to DAC regimen for 3 weeks. An amount of 10 mg/kg Rg1 significantly improved chemobrain-like behavior in water maze test. In vivo neuroimaging revealed that Rg1 co-treatment reversed DAC-induced decreases in prefrontal and hippocampal neuronal activity and ameliorated cortical neuronal dendritic spine elimination. It normalized DAC-caused abnormalities in the expression of multiple neuroplasticity biomarkers in the two brain regions. Rg1 suppressed DAC-induced elevation of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but increased levels of the anti-inflammatory cytokines IL-4 and IL-10 in multiple sera and brain tissues. Rg1 also modulated cytokine mediators and inhibited DAC-induced microglial polarization from M2 to M1 phenotypes. In in vitro experiments, while impaired viability of PC12 neuroblastic cells and hyperactivation of BV-2 microglial cells, a model of neuroinflammation, were observed in the presence of DAC, Rg1 co-treatment strikingly reduced DAC’s neurotoxic effects and neuroinflammatory response. These results indicate that Rg1 exerts its anti-chemobrain effect in an association with the inhibition of neuroinflammation by modulating microglia-mediated cytokines and the related upstream mediators, protecting neuronal activity and promoting neuroplasticity in particular brain regions associated with cognition processing.


Ginsenoside Rg1 Chemobrain Cytokines Neuroinflammation Neuroplasticity In vivo neuroimaging 



This study was supported by General Research Fund (GRF) of Research Grant Council of HKSAR (17115017 for Z.-J.Z.).

Compliance with Ethical Standards

Conflict of Interest Statement

All authors have no conflicts of interest with this work.

Supplementary material

12035_2019_1474_MOESM1_ESM.docx (537 kb)
ESM 1 (DOCX 536 kb)


  1. 1.
    Wefel JS, Schagen SB (2012) Chemotherapy-related cognitive dysfunction. Curr Neurol Neurosci Rep 12(3):267–275. CrossRefPubMedGoogle Scholar
  2. 2.
    Deprez S, Amant F, Smeets A, Peeters R, Leemans A, Van Hecke W, Verhoeven JS, Christiaens MR et al (2012) Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol Off J Am Soc Clin Oncol 30(3):274–281. CrossRefGoogle Scholar
  3. 3.
    Taillibert S, Le Rhun E, Chamberlain MC (2016) Chemotherapy-related neurotoxicity. Curr Neurol Neurosci Rep 16(9):81. CrossRefPubMedGoogle Scholar
  4. 4.
    Yao C, Bernstein LJ, Rich JB (2017) Executive functioning impairment in women treated with chemotherapy for breast cancer: a systematic review. Breast Cancer Res Treat 166(1):15–28. CrossRefPubMedGoogle Scholar
  5. 5.
    Wang XM, Walitt B, Saligan L, Tiwari AF, Cheung CW, Zhang ZJ (2015) Chemobrain: a critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy. Cytokine 72(1):86–96. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Tangpong J, Cole MP, Sultana R, Joshi G, Estus S, Vore M, St Clair W, Ratanachaiyavong S et al (2006) Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity. Neurobiol Dis 23(1):127–139. CrossRefPubMedGoogle Scholar
  7. 7.
    Cheung YT, Ng T, Shwe M, Ho HK, Foo KM, Cham MT, Lee JA, Fan G et al (2015) Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study. Annals of oncology : Official journal of the European society for. Med Oncol 26(7):1446–1451. CrossRefGoogle Scholar
  8. 8.
    Shi DD, Dong CM, Ho LC, Lam CTW, Zhou XD, Wu EX, Zhou ZJ, Wang XM et al (2018) Resveratrol, a natural polyphenol, prevents chemotherapy-induced cognitive impairment: involvement of cytokine modulation and neuroprotection. Neurobiol Dis 114:164–173. CrossRefPubMedGoogle Scholar
  9. 9.
    Gao Y, Chu S, Li J, Li J, Zhang Z, Xia C, Heng Y, Zhang M et al (2015) Anti-inflammatory function of ginsenoside Rg1 on alcoholic hepatitis through glucocorticoid receptor related nuclear factor-kappa B pathway. J Ethnopharmacol 173:231–240. CrossRefPubMedGoogle Scholar
  10. 10.
    Gao Y, Chu S, Zhang Z, Chen N (2017) Hepataprotective effects of ginsenoside Rg1—a review. J Ethnopharmacol 206:178–183. CrossRefPubMedGoogle Scholar
  11. 11.
    Li F, Wu X, Li J, Niu Q (2016) Ginsenoside Rg1 ameliorates hippocampal long-term potentiation and memory in an Alzheimer's disease model. Mol Med Rep 13(6):4904–4910. CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang X, Wang J, Xing Y, Gong L, Li H, Wu Z, Li Y, Wang J et al (2012) Effects of ginsenoside Rg1 or 17beta-estradiol on a cognitively impaired, ovariectomized rat model of Alzheimer's disease. Neuroscience 220:191–200. CrossRefPubMedGoogle Scholar
  13. 13.
    Au HJ, Golmohammadi K, Younis T, Verma S, Chia S, Fassbender K, Jacobs P (2009) Cost-effectiveness analysis of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-positive breast cancer: modeling the downstream effects. Breast Cancer Res Treat 114(3):579–587. CrossRefPubMedGoogle Scholar
  14. 14.
    Mancuso JJ, Chen Y, Li X, Xue Z, Wong ST (2013) Methods of dendritic spine detection: from Golgi to high-resolution optical imaging. Neuroscience 251:129–140. CrossRefPubMedGoogle Scholar
  15. 15.
    Sau Wan Lai C (2014) Intravital imaging of dendritic spine plasticity. Intravital 3(3):e944439. CrossRefPubMedGoogle Scholar
  16. 16.
    Lai CS, Franke TF, Gan WB (2012) Opposite effects of fear conditioning and extinction on dendritic spine remodelling. Nature 483(7387):87–91. CrossRefPubMedGoogle Scholar
  17. 17.
    Stansley B, Post J, Hensley K (2012) A comparative review of cell culture systems for the study of microglial biology in Alzheimer's disease. J Neuroinflammation 9:115. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Franco R, Fernandez-Suarez D (2015) Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol 131:65–86. CrossRefPubMedGoogle Scholar
  19. 19.
    Yang L, Zhang J, Zheng K, Shen H, Chen X (2014) Long-term ginsenoside Rg1 supplementation improves age-related cognitive decline by promoting synaptic plasticity associated protein expression in C57BL/6J mice. J Gerontol A Biol Sci Med Sci 69(3):282–294. CrossRefPubMedGoogle Scholar
  20. 20.
    Fang F, Chen X, Huang T, Lue LF, Luddy JS, Yan SS (2012) Multi-faced neuroprotective effects of ginsenoside Rg1 in an Alzheimer mouse model. Biochim Biophys Acta 1822(2):286–292. CrossRefPubMedGoogle Scholar
  21. 21.
    Jin Y, Peng J, Wang X, Zhang D, Wang T (2017) Ameliorative effect of ginsenoside Rg1 on lipopolysaccharide-induced cognitive impairment: role of cholinergic system. Neurochem Res 42(5):1299–1307. CrossRefPubMedGoogle Scholar
  22. 22.
    Song XY, Hu JF, Chu SF, Zhang Z, Xu S, Yuan YH, Han N, Liu Y et al (2013) Ginsenoside Rg1 attenuates okadaic acid induced spatial memory impairment by the GSK3beta/tau signaling pathway and the Abeta formation prevention in rats. Eur J Pharmacol 710(1–3):29–38. CrossRefPubMedGoogle Scholar
  23. 23.
    Wang Q, Sun LH, Jia W, Liu XM, Dang HX, Mai WL, Wang N, Steinmetz A et al (2010) Comparison of ginsenosides Rg1 and Rb1 for their effects on improving scopolamine-induced learning and memory impairment in mice. Phytother Res 24(12):1748–1754. CrossRefPubMedGoogle Scholar
  24. 24.
    Zhu J, Mu X, Zeng J, Xu C, Liu J, Zhang M, Li C, Chen J et al (2014) Ginsenoside Rg1 prevents cognitive impairment and hippocampus senescence in a rat model of D-galactose-induced aging. PLoS One 9(6):e101291. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Simo M, Rifa-Ros X, Rodriguez-Fornells A, Bruna J (2013) Chemobrain: a systematic review of structural and functional neuroimaging studies. Neurosci Biobehav Rev 37(8):1311–1321. CrossRefPubMedGoogle Scholar
  26. 26.
    Yang M, Moon C (2013) Neurotoxicity of cancer chemotherapy. Neural Regen Res 8(17):1606–1614. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Xue W, Liu Y, Qi WY, Gao Y, Li M, Shi AX, Li KX (2016) Pharmacokinetics of ginsenoside Rg1 in rat medial prefrontal cortex, hippocampus, and lateral ventricle after subcutaneous administration. J Asian Nat Prod Res 18(6):587–595. CrossRefPubMedGoogle Scholar
  28. 28.
    Rubin RD, Schwarb H, Lucas HD, Dulas MR, Cohen NJ (2017) Dynamic hippocampal and prefrontal contributions to memory processes and representations blur the boundaries of traditional cognitive domains. Brain Sci 7 (7).
  29. 29.
    Mohler H (2007) Molecular regulation of cognitive functions and developmental plasticity: impact of GABAA receptors. J Neurochem 102(1):1–12. CrossRefPubMedGoogle Scholar
  30. 30.
    Sachser RM, Haubrich J, Lunardi PS, de Oliveira Alvares L (2017) Forgetting of what was once learned: exploring the role of postsynaptic ionotropic glutamate receptors on memory formation, maintenance, and decay. Neuropharmacology 112(Pt A):94–103. CrossRefPubMedGoogle Scholar
  31. 31.
    Cervetto C, Taccola G (2008) GABAA and strychnine-sensitive glycine receptors modulate N-methyl-D-aspartate-evoked acetylcholine release from rat spinal motoneurons: a possible role in neuroprotection. Neuroscience 154(4):1517–1524. CrossRefPubMedGoogle Scholar
  32. 32.
    Mook-Jung I, Hong HS, Boo JH, Lee KH, Yun SH, Cheong MY, Joo I, Huh K et al (2001) Ginsenoside Rb1 and Rg1 improve spatial learning and increase hippocampal synaptophysin level in mice. J Neurosci Res 63(6):509–515. CrossRefPubMedGoogle Scholar
  33. 33.
    Qi D, Zhu Y, Wen L, Liu Q, Qiao H (2009) Ginsenoside Rg1 restores the impairment of learning induced by chronic morphine administration in rats. J Psychopharmacol 23(1):74–83. CrossRefPubMedGoogle Scholar
  34. 34.
    Shi YQ, Huang TW, Chen LM, Pan XD, Zhang J, Zhu YG, Chen XC (2010) Ginsenoside Rg1 attenuates amyloid-beta content, regulates PKA/CREB activity, and improves cognitive performance in SAMP8 mice. J Alzheimers Dis 19(3):977–989. CrossRefPubMedGoogle Scholar
  35. 35.
    Wang XY, Zhang JT (2001) Effects of ginsenoside Rg1 on synaptic plasticity of freely moving rats and its mechanism of action. Acta Pharmacol Sin 22(7):657–662PubMedGoogle Scholar
  36. 36.
    Zhu G, Wang Y, Li J, Wang J (2015) Chronic treatment with ginsenoside Rg1 promotes memory and hippocampal long-term potentiation in middle-aged mice. Neuroscience 292:81–89. CrossRefPubMedGoogle Scholar
  37. 37.
    Omeragic A, Hoque MT, Choi UY, Bendayan R (2017) Peroxisome proliferator-activated receptor-gamma: potential molecular therapeutic target for HIV-1-associated brain inflammation. J Neuroinflammation 14(1):183. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Martin H (2010) Role of PPAR-gamma in inflammation. Prospects for therapeutic intervention by food components. Mutat Res 690(1–2):57–63CrossRefGoogle Scholar
  39. 39.
    Zhang Y, Chen C, Jiang Y, Wang S, Wu X, Wang K (2017) PPARgamma coactivator-1alpha (PGC-1alpha) protects neuroblastoma cells against amyloid-beta (Abeta) induced cell death and neuroinflammation via NF-kappaB pathway. BMC Neurosci 18(1):69. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Clark RB, Bishop-Bailey D, Estrada-Hernandez T, Hla T, Puddington L, Padula SJ (2000) The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J Immunol 164(3):1364–1371CrossRefGoogle Scholar
  41. 41.
    Li Y, Guan Y, Wang Y, Yu CL, Zhai FG, Guan LX (2017) Neuroprotective effect of the ginsenoside Rg1 on cerebral ischemic injury in vivo and in vitro is mediated by PPARgamma-regulated antioxidative and anti-inflammatory pathways. Evid Based Complement Alternat Med 2017:7842082. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Yang Y, Li X, Zhang L, Liu L, Jing G, Cai H (2015) Ginsenoside Rg1 suppressed inflammation and neuron apoptosis by activating PPARgamma/HO-1 in hippocampus in rat model of cerebral ischemia–reperfusion injury. Int J Clin Exp Pathol 8(3):2484–2494PubMedPubMedCentralGoogle Scholar
  43. 43.
    Quan Q, Wang J, Li X, Wang Y (2013) Ginsenoside Rg1 decreases Abeta(1-42) level by upregulating PPARgamma and IDE expression in the hippocampus of a rat model of Alzheimer's disease. PLoS One 8(3):e59155. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Streit WJ, Mrak RE, Griffin WS (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 1(1):14. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Peng H, Li H, Sheehy A, Cullen P, Allaire N, Scannevin RH (2016) Dimethyl fumarate alters microglia phenotype and protects neurons against proinflammatory toxic microenvironments. J Neuroimmunol 299:35–44. CrossRefPubMedGoogle Scholar
  46. 46.
    Chae JW, Ng T, Yeo HL, Shwe M, Gan YX, Ho HK, Chan A (2016) Impact of TNF-alpha (rs1800629) and IL-6 (rs1800795) polymorphisms on cognitive impairment in Asian breast cancer patients. PLoS One 11:e0164204CrossRefGoogle Scholar
  47. 47.
    Cheung YT, Ng T, Shwe M, Ho HK, Foo KM, Cham MT, Lee JA, Fan G et al (2015) Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study. Ann Oncol 26:1446–1451CrossRefGoogle Scholar
  48. 48.
    Ganz PA, Bower JE, Kwan L, Castellon SA, Silverman DH, Geist C, Breen EC, Irwin MR et al (2013) Does tumor necrosis factor-alpha (TNF-alpha) play a role in post-chemotherapy cerebral dysfunction? Brain Behav Immun 30(Suppl):S99–S108CrossRefGoogle Scholar
  49. 49.
    Jiang B, Xiong Z, Yang J, Wang W, Wang Y, Hu ZL, Wang F, Chen JG (2012) Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus. Br J Pharmacol 166:1872–1887. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Mou Z, Huang Q, Chu SF, Zhang MJ, Hu JF, Chen NH, Zhang JT (2017) Antidepressive effects of ginsenoside Rg1 via regulation of HPA and HPG axis. Biomed Pharmacother 92:962–971CrossRefGoogle Scholar
  51. 51.
    Heng Y, Zhang QS, Mu Z, Hu JF, Yuan YH, Chen NH (2016) Ginsenoside Rg1 attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced parkinsonism mouse model by targeting α-synuclein abnormalities in the substantia nigra. Toxicol Lett 243:7–21CrossRefGoogle Scholar
  52. 52.
    Sun XC, Ren XF, Chen L, Gao XQ, Xie JX, Chen WF (2016) Glucocorticoid receptor is involved in the neuroprotective effect of ginsenoside Rg1 against inflammation-induced dopaminergic neuronal degeneration in substantia nigra. J Steroid Biochem Mol Biol 155:94–103CrossRefGoogle Scholar
  53. 53.
    Wang Z, Zhu K, Chen L, Ou Yang L, Huang Y, Zhao Y (2015) Preventive effects of ginsenoside Rg1 on post-traumatic stress disorder (PTSD)-like behavior in male C57/B6 mice. Neurosci Lett 605:24–28CrossRefGoogle Scholar
  54. 54.
    Chen S, Wang Z, Huang Y, O'Barr SA, Wong RA, Yeung S, Chow MS (2014) Ginseng and anticancer drug combination to improve cancer chemotherapy: a critical review. Evid Based Complement Alternat Med 2014:168940. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Cui Y, Shu XO, Gao YT, Cai H, Tao MH, Zheng W (2006) Association of ginseng use with survival and quality of life among breast cancer patients. Am J Epidemiol 163(7):645–653. CrossRefPubMedGoogle Scholar
  56. 56.
    Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7:27–31. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Helms S (2004) Cancer prevention and therapeutics: Panax ginseng. Altern Med Rev 9(3):259–274PubMedGoogle Scholar
  58. 58.
    Lee SM, Bae BS, Park HW, Ahn NG, Cho BG, Cho YL, Kwak YS (2015) Characterization of Korean red ginseng (Panax ginseng Meyer): history, preparation method, and chemical composition. J Ginseng Res 39(4):384–391. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Dong-Dong Shi
    • 1
  • Yu-Hua Huang
    • 2
  • Cora Sau Wan Lai
    • 2
  • Celia M. Dong
    • 3
  • Leon C. Ho
    • 3
  • Xiao-Yang Li
    • 2
  • Ed X. Wu
    • 3
  • Qi Li
    • 4
  • Xiao-Min Wang
    • 5
  • Yong-Jun Chen
    • 6
  • Sookja Kim Chung
    • 2
  • Zhang-Jin Zhang
    • 1
    Email author
  1. 1.School of Chinese Medicine, LKS Faculty of MedicineThe University of Hong KongHong KongChina
  2. 2.School of Biomedical Sciences, State Key Laboratory of Pharmaceutical Biotechnology, LKS Faculty of MedicineThe University of Hong KongHong KongChina
  3. 3.Laboratory of Biomedical Imaging and Signal Processing, Department of Electrical and Electronic EngineeringThe University of Hong KongHong KongChina
  4. 4.Department of Psychiatry, State Key Laboratory of Cognitive and Brain Sciences, HKU-SIRIThe University of Hong KongHong KongChina
  5. 5.Department of Anesthesiology, LKS Faculty of MedicineThe University of Hong KongHong KongChina
  6. 6.South China Research Center for Acupuncture and MoxibustionGuangzhou University of Chinese MedicineGuangzhouChina

Personalised recommendations