Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Ginsenoside Rg1 in neurological diseases: From bench to bedside

Acta Pharmacologica Sinica volume 44, pages 913–930 (2023)Cite this article

Abstract

Ginseng has been used in China as a superior medicinal material for thousands of years that can nourish the five internal organs, calm the mind and benefit wisdom. Due to its anti-inflammatory, antioxidant and neuroprotective activities, one of the active components of ginseng, ginsenoside Rg1, has been extensively investigated in the remedy of brain disorders, especially dementia and depression. In this review, we summarized the research progress on the action mechanisms of Rg1 ameliorating depression-like behaviors, including inhibition of hyperfunction of hypothalamic-pituitary-adrenal (HPA) axis, regulation of synaptic plasticity and gut flora. Rg1 may alleviate Alzheimer’s disease in the early phase, as well as in the middle-late phases through repairing dendrite, axon and microglia- and astrocyte-related inflammations. We also proposed that Rg1 could regulate memory state (the imbalance of working and aversive memory) caused by distinct stimuli. These laboratory studies would further the clinical trials on Rg1. From the prospective of drug development, we discussed the limitations of the present investigations and proposed our ideas to increase permeability and bioavailability of Rg1. Taken together, Rg1 has the potential to treat neuropsychiatric disorders, but a future in-depth investigation of the mechanisms is still required. In addition, drug development will benefit from the clinical trials in one specific neuropsychiatric disorder.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The mechanism of antidepressant effect of Rg1.
Fig. 2: Potential targets and molecular docking of Rg1 against depression.
Fig. 3: The mechanisms involved in the effects of Rg1 against Alzheimer’s disease.
Fig. 4: Potential targets and molecular docking of Rg1 against AD.
Fig. 5: Effects of Rg1 on learning and memory functions. Rg1 could regulate the learning and memory function in pathological state.
Fig. 6: “Drug-disease” targets of Rg1, depression and AD, and GO (Top 10) and KEGG (Top 30) enrichment analysis of common targets.

Similar content being viewed by others

References

  1. Sanacora G, Yan Z, Popoli M. The stressed synapse 2.0: Pathophysiological mechanisms in stress-related neuropsychiatric disorders. Nat Rev Neurosci. 2022;23:86–103.

    Article  CAS  PubMed  Google Scholar 

  2. Dorsey ER, Sherer T, Okun MS, Bloem BR. The emerging evidence of the Parkinson pandemic. J Parkinsons Dis. 2018;8:S3–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Group GBDNDC. Global, regional, and national burden of neurological disorders during 1990-2015: A systematic analysis for the global burden of disease study 2015. Lancet Neurol. 2017;16:877–97.

    Article  Google Scholar 

  4. McCarron RM, Shapiro B, Rawles J, Luo J. Depression. Ann Intern Med. 2021;174:ITC65–ITC80.

    Article  PubMed  Google Scholar 

  5. Yang HS. Human genetics clarifies the relationship between depression and Alzheimer’s disease. Biol Psychiatry. 2022;92:2–4.

    Article  PubMed  Google Scholar 

  6. Zhang C, Wang L, Xu Y, Huang Y, Huang J, Zhu J, et al. Discovery of novel dual RAGE/SERT inhibitors for the potential treatment of the comorbidity of Alzheimer’s disease and depression. Eur J Med Chem. 2022;236:114347.

    Article  CAS  PubMed  Google Scholar 

  7. Cummings J, Feldman HH, Scheltens P. The “rights” of precision drug development for Alzheimer’s disease. Alzheimers Res Ther. 2019;11:76.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yang S, Zhu G. 7,8-dihydroxyflavone and neuropsychiatric disorders: A translational perspective from the mechanism to drug development. Curr Neuropharmacol. 2022;20:1479–97.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jiang B, Xiong Z, Yang J, Wang W, Wang Y, Hu ZL, et al. Antidepressant-like effects of ginsenoside rg1 are due to activation of the bdnf signalling pathway and neurogenesis in the hippocampus. Br J Pharmacol. 2012;166:1872–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yi YS. New mechanisms of ginseng saponin-mediated anti-inflammatory action via targeting canonical inflammasome signaling pathways. J Ethnopharmacol. 2021;278:114292.

    Article  CAS  PubMed  Google Scholar 

  11. Ai PH, Chen S, Liu XD, Zhu XN, Pan YB, Feng DF, et al. Paroxetine ameliorates prodromal emotional dysfunction and late-onset memory deficit in Alzheimer’s disease mice. Transl Neurodegener. 2020;9:18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kawakami I, Iga JI, Takahashi S, Lin YT, Fujishiro H. Towards an understanding of the pathological basis of senile depression and incident dementia: Implications for treatment. Psychiatry Clin Neurosci. 2022. https://doi.org/10.1111/pcn.13485

    Article  PubMed  PubMed Central  Google Scholar 

  13. Juszczyk G, Mikulska J, Kasperek K, Pietrzak D, Mrozek W, Herbet M. Chronic stress and oxidative stress as common factors of the pathogenesis of depression and alzheimer’s disease: The role of antioxidants in prevention and treatment. Antioxidants (Basel). 2021;10:1439.

    Article  CAS  PubMed  Google Scholar 

  14. Linnemann C, Lang UE. Pathways connecting late-life depression and dementia. Front Pharmacol. 2020;11:279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li C, Sui C, Wang W, Yan J, Deng N, Du X, et al. Baicalin attenuates oxygen-glucose deprivation/reoxygenation-induced injury by modulating the BDNF-TRKB/PI3K/AKT and MAPK/ERK1/2 signaling axes in neuron-astrocyte cocultures. Front Pharmacol. 2021;12:599543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang ZH, Xiang J, Liu X, Yu SP, Manfredsson FP, Sandoval IM, et al. Deficiency in BDNF/TrkB neurotrophic activity stimulates delta-secretase by upregulating C/EBPbeta in Alzheimer’s disease. Cell Rep. 2019;28:655–69.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lim JY, Reighard CP, Crowther DC. The pro-domains of neurotrophins, including BDNF, are linked to Alzheimer’s disease through a toxic synergy with abeta. Hum Mol Genet. 2015;24:3929–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Guan W, Xu DW, Ji CH, Wang CN, Liu Y, Tang WQ, et al. Hippocampal miR-206-3p participates in the pathogenesis of depression via regulating the expression of BDNF. Pharmacol Res. 2021;174:105932.

    Article  CAS  PubMed  Google Scholar 

  19. Fani G, Mannini B, Vecchi G, Cascella R, Cecchi C, Dobson CM, et al. Abeta oligomers dysregulate calcium homeostasis by mechanosensitive activation of AMPA and NMDA receptors. ACS Chem Neurosci. 2021;12:766–81.

    Article  CAS  PubMed  Google Scholar 

  20. Miyamoto T, Stein L, Thomas R, Djukic B, Taneja P, Knox J, et al. Phosphorylation of tau at Y18, but not tau-fyn binding, is required for Tau to modulate nmda receptor-dependent excitotoxicity in primary neuronal culture. Mol Neurodegener. 2017;12:41.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Song Z, Bian Z, Zhang Z, Wang X, Zhu A, Zhu G. Astrocytic kir4.1 regulates nmdar/calpain signaling axis in lipopolysaccharide-induced depression-like behaviors in mice. Toxicol Appl Pharmacol. 2021;429:115711.

    Article  CAS  PubMed  Google Scholar 

  22. Arimon M, Takeda S, Post KL, Svirsky S, Hyman BT, Berezovska O. Oxidative stress and lipid peroxidation are upstream of amyloid pathology. Neurobiol Dis. 2015;84:109–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pena-Bautista C, Tirle T, Lopez-Nogueroles M, Vento M, Baquero M, Chafer-Pericas C. Oxidative damage of DNA as early marker of Alzheimer’s disease. Int J Mol Sci. 2019;20:6136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mahmoud AM, Alexander MY, Tutar Y, Wilkinson FL, Venditti A. Oxidative stress in metabolic disorders and drug-induced injury: The potential role of Nrf2 and PPARs activators. Oxid Med Cell Longev. 2017;2017:2508909.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Song L, Wu X, Wang J, Guan Y, Zhang Y, Gong M, et al. Antidepressant effect of catalpol on corticosterone-induced depressive-like behavior involves the inhibition of HPA axis hyperactivity, central inflammation and oxidative damage probably via dual regulation of NF-kappab and Nrf2. Brain Res Bull. 2021;177:81–91.

    Article  CAS  PubMed  Google Scholar 

  26. Diniz BS, Mendes-Silva AP, Silva LB, Bertola L, Vieira MC, Ferreira JD, et al. Oxidative stress markers imbalance in late-life depression. J Psychiatr Res. 2018;102:29–33.

    Article  PubMed  Google Scholar 

  27. Shen F, Song Z, Xie P, Li L, Wang B, Peng D, et al. Polygonatum sibiricum polysaccharide prevents depression-like behaviors by reducing oxidative stress, inflammation, and cellular and synaptic damage. J Ethnopharmacol. 2021;275:114164.

    Article  CAS  PubMed  Google Scholar 

  28. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chetelat G, Teunissen CE, et al. Alzheimer’s disease. Lancet. 2021;397:1577–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang X, Gao F, Xu W, Cao Y, Wang J, Zhu G. Depichering the effects of Astragaloside IV on AD-like phenotypes: A systematic and experimental investigation. Oxid Med Cell Longev. 2021;2021:1020614.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Min W, Liu C, Yang Y, Sun X, Zhang B, Xu L, et al. Alterations in hypothalamic-pituitary-adrenal/thyroid (HPA/HPT) axes correlated with the clinical manifestations of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39:206–11.

    Article  CAS  PubMed  Google Scholar 

  31. Song Z, Shen F, Zhang Z, Wu S, Zhu G. Calpain inhibition ameliorates depression-like behaviors by reducing inflammation and promoting synaptic protein expression in the hippocampus. Neuropharmacology. 2020;174:108175.

    Article  CAS  PubMed  Google Scholar 

  32. Mahar I, Bambico FR, Mechawar N, Nobrega JNStress. serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neurosci Biobehav Rev. 2014;38:173–92.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  PubMed  Google Scholar 

  34. O’Connor DB, Thayer JF, Vedhara K. Stress and health: A review of psychobiological processes. Annu Rev Psychol. 2021;72:663–88.

    Article  PubMed  Google Scholar 

  35. Dwyer JB, Aftab A, Radhakrishnan R, Widge A, Rodriguez CI, Carpenter LL, et al. Hormonal treatments for major depressive disorder: State of the art. Am J Psychiatry. 2020;177:686–705.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Mou Z, Huang Q, Chu SF, Zhang MJ, Hu JF, Chen NH, et al. Antidepressive effects of ginsenoside Rg1 via regulation of HPA and HPG axis. Biomed Pharmacother. 2017;92:962–71.

    Article  CAS  PubMed  Google Scholar 

  37. Zheng X, Liang Y, Kang A, Ma SJ, Xing L, Zhou YY, et al. Peripheral immunomodulation with ginsenoside Rg1 ameliorates neuroinflammation-induced behavioral deficits in rats. Neuroscience. 2014;256:210–22.

    Article  CAS  PubMed  Google Scholar 

  38. Wang YT, Wang XL, Feng ST, Chen NH, Wang ZZ, Zhang Y. Novel rapid-acting glutamatergic modulators: Targeting the synaptic plasticity in depression. Pharmacol Res. 2021;171:105761.

    Article  CAS  PubMed  Google Scholar 

  39. Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fan C, Song Q, Wang P, Li Y, Yang M, Yu SY. Neuroprotective effects of ginsenoside-Rg1 against depression-like behaviors via suppressing glial activation, synaptic deficits, and neuronal apoptosis in rats. Front Immunol. 2018;9:2889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu Z, Qi Y, Cheng Z, Zhu X, Fan C, Yu SY. The effects of ginsenoside Rg1 on chronic stress induced depression-like behaviors, BDNF expression and the phosphorylation of PKA and CREB in rats. Neuroscience. 2016;322:358–69.

    Article  CAS  PubMed  Google Scholar 

  42. Zhu X, Gao R, Liu Z, Cheng Z, Qi Y, Fan C, et al. Ginsenoside Rg1 reverses stress-induced depression-like behaviours and brain-derived neurotrophic factor expression within the prefrontal cortex. Eur J Neurosci. 2016;44:1878–85.

    Article  PubMed  Google Scholar 

  43. Wang J, Shen F, Zhang Z, Zhu G. Effects of ginsenoside Rg1 on depression-like behaviors, expression of hippocampal synaptic proteins and activation of glial cells in stressed mice. J Biol. 2021;38:26–30.

    CAS  Google Scholar 

  44. Kaufmann FN, Menard C. Inflamed astrocytes: A path to depression led by menin. Neuron. 2018;100:511–3.

    Article  CAS  PubMed  Google Scholar 

  45. Zheng X, Ma S, Kang A, Wu M, Wang L, Wang Q, et al. Chemical dampening of Ly6C(hi) monocytes in the periphery produces anti-depressant effects in mice. Sci Rep. 2016;6:19406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jin C, Wang ZZ, Zhou H, Lou YX, Chen J, Zuo W, et al. Ginsenoside Rg1-induced antidepressant effects involve the protection of astrocyte gap junctions within the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry. 2017;75:183–91.

    Article  CAS  PubMed  Google Scholar 

  47. Wang H, Yang Y, Yang S, Ren S, Feng J, Liu Y, et al. Ginsenoside Rg1 ameliorates neuroinflammation via suppression of connexin43 ubiquitination to attenuate depression. Front Pharmacol. 2021;12:709019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Xia CY, Chu SF, Zhang S, Gao Y, Ren Q, Lou YX, et al. Ginsenoside Rg1 alleviates corticosterone-induced dysfunction of gap junctions in astrocytes. J Ethnopharmacol. 2017;208:207–13.

    Article  CAS  PubMed  Google Scholar 

  49. Lou YX, Wang ZZ, Xia CY, Mou Z, Ren Q, Liu DD, et al. The protective effect of ginsenoside Rg1 on depression may benefit from the gap junction function in hippocampal astrocytes. Eur J Pharmacol. 2020;882:173309.

    Article  CAS  PubMed  Google Scholar 

  50. Xia CY, Wang ZZ, Wang HQ, Ren SY, Lou YX, Jin C, et al. Connexin 43: A novel ginsenoside Rg1-sensitive target in a rat model of depression. Neuropharmacology. 2020;170:108041.

    Article  CAS  PubMed  Google Scholar 

  51. Wang HQ, Yang SW, Gao Y, Liu YJ, Li X, Ai QD, et al. Novel antidepressant mechanism of ginsenoside Rg1: Regulating biosynthesis and degradation of connexin43. J Ethnopharmacol. 2021;278:114212.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang Z, Deng T, Wu M, Zhu A, Zhu G. Botanicals as modulators of depression and mechanisms involved. Chin Med. 2019;14:24.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Li Y, Wang L, Wang P, Fan C, Zhang P, Shen J, et al. Ginsenoside-Rg1 rescues stress-induced depression-like behaviors via suppression of oxidative stress and neural inflammation in rats. Oxid Med Cell Longev. 2020;2020:2325391.

    PubMed  PubMed Central  Google Scholar 

  54. Li J, Huang Q, Chen J, Qi H, Liu J, Chen Z, et al. Neuroprotective potentials of panax ginseng against Alzheimer’s disease: A review of preclinical and clinical evidences. Front Pharmacol. 2021;12:688490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hampel H, Hardy J, Blennow K, Chen C, Perry G, Kim SH, et al. The amyloid-beta pathway in Alzheimer’s disease. Mol Psychiatry. 2021;26:5481–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhang H, Su Y, Sun Z, Chen M, Han Y, Li Y, et al. Ginsenoside Rg1 alleviates Abeta deposition by inhibiting NADPH oxidase 2 activation in App/PS1 mice. J Ginseng Res. 2021;45:665–75.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Huang L, Liu LF, Liu J, Dou L, Wang GY, Liu XQ, et al. Ginsenoside Rg1 protects against neurodegeneration by inducing neurite outgrowth in cultured hippocampal neurons. Neural Regen Res. 2016;11:319–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yang Y, Li S, Huang H, Lv J, Chen S, Pires Dias AC, et al. Comparison of the protective effects of ginsenosides Rb1 and Rg1 on improving cognitive deficits in SAMP8 mice based on anti-neuroinflammation mechanism. Front Pharmacol. 2020;11:834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Quan Q, Li X, Feng J, Hou J, Li M, Zhang B. Ginsenoside Rg1 reduces β amyloid levels by inhibiting CDK5 induced PPARγ phosphorylation in a neuron model of Alzheimer’s disease. Mol Med Rep. 2020;22:3277–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Quan Q, Wang J, Li X, Wang Y. 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. 2013;8:e59155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sahoo BR, Panda PK, Liang W, Tang WJ, Ahuja R, Ramamoorthy A. Degradation of Alzheimer’s amyloid-beta by a catalytically inactive insulin-degrading enzyme. J Mol Biol. 2021;433:166993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wegmann S, Biernat J, Mandelkow E. A current view on tau protein phosphorylation in Alzheimer’s disease. Curr Opin Neurobiol. 2021;69:131–8.

    Article  CAS  PubMed  Google Scholar 

  63. Brier MR, Gordon B, Friedrichsen K, McCarthy J, Stern A, Christensen J, et al. Tau and abeta imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med. 2016;8:338ra66.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Li X, Li M, Li Y, Quan Q, Wang J. Cellular and molecular mechanisms underlying the action of ginsenoside Rg1 against Alzheimer’s disease. Neural Regen Res. 2012;7:2860–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Angelucci F, Cechova K, Amlerova J, Hort J. Antibiotics, gut microbiota, and Alzheimer’s disease. J Neuroinflammation. 2019;16:108.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Wang L, Lu J, Zeng Y, Guo Y, Wu C, Zhao H, et al. Improving Alzheimer’s disease by altering gut microbiota in tree shrews with ginsenoside Rg1. FEMS Microbiol Lett. 2020;367:fnaa011.

    Article  CAS  PubMed  Google Scholar 

  67. Guo Y, Wang L, Lu J, Jiao J, Yang Y, Zhao H, et al. Ginsenoside Rg1 improves cognitive capability and affects the microbiota of large intestine of tree shrew model for Alzheimer’s disease. Mol Med Rep. 2021;23:291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Janelidze S, Mattsson N, Stomrud E, Lindberg O, Palmqvist S, Zetterberg H, et al. CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease. Neurology. 2018;91:e867–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Brigas HC, Ribeiro M, Coelho JE, Gomes R, Gomez-Murcia V, Carvalho K, et al. IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer’s disease. Cell Rep. 2021;36:109574.

    Article  CAS  PubMed  Google Scholar 

  70. Shukla D, Mandal PK, Tripathi M, Vishwakarma G, Mishra R, Sandal K. Quantitation of in vivo brain glutathione conformers in cingulate cortex among age-matched control, MCI, and AD patients using MEGA-PRESS. Hum Brain Mapp. 2020;41:194–217.

    Article  PubMed  Google Scholar 

  71. Song T, Song X, Zhu C, Patrick R, Skurla M, Santangelo I, et al. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer’s disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies. Ageing Res Rev. 2021;72:101503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhang Y, Ding S, Chen Y, Sun Z, Zhang J, Han Y, et al. Ginsenoside Rg1 alleviates lipopolysaccharide-induced neuronal damage by inhibiting NLRP1 inflammasomes in HT22 cells. Exp Ther Med. 2021;22:782.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Xu TZ, Shen XY, Sun LL, Chen YL, Zhang BQ, Huang DK, et al. Ginsenoside Rg1 protects against H2 O2 induced neuronal damage due to inhibition of the NLRP1 inflammasome signalling pathway in hippocampal neurons in vitro. Int J Mol Med. 2019;43:717–26.

    CAS  PubMed  Google Scholar 

  74. Zhang Y, Hu W, Zhang B, Yin Y, Zhang J, Huang D, et al. Ginsenoside Rg1 protects against neuronal degeneration induced by chronic dexamethasone treatment by inhibiting NLRP-1 inflammasomes in mice. Int J Mol Med. 2017;40:1134–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhao BS, Liu Y, Gao XY, Zhai HQ, Guo JY, Wang XY. Effects of ginsenoside Rg1 on the expression of toll-like receptor 3, 4 and their signalling transduction factors in the NG108-15 murine neuroglial cell line. Molecules. 2014;19:16925–36.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Kwan KKL, Yun H, Dong TTX, Tsim KWK. Ginsenosides attenuate bioenergetics and morphology of mitochondria in cultured PC12 cells under the insult of amyloid beta-peptide. J Ginseng Res. 2021;45:473–81.

    Article  PubMed  Google Scholar 

  77. Du K, Yang S, Wang J, Zhu G. Acupuncture interventions for Alzheimer’s disease and vascular cognitive disorders: A review of mechanisms. Oxid Med Cell Longev. 2022;2022:6080282.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Shen F, Wang J, Gao F, Wang J, Zhu G. Ginsenoside Rg1 prevents cognitive impairment and hippocampal neuronal apoptosis in experimental vascular dementia mice by promoting GPR30 expression. Neural Plast. 2021;2021:2412220.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Maddox SA, Hartmann J, Ross RA, Ressler KJ. Deconstructing the gestalt: Mechanisms of fear, threat, and trauma memory encoding. Neuron. 2019;102:60–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhang Z, Song Z, Shen F, Xie P, Wang J, Zhu AS, et al. Ginsenoside Rg1 prevents ptsd-like behaviors in mice through promoting synaptic proteins, reducing Kir4.1 and TNF-alpha in the hippocampus. Mol Neurobiol. 2021;58:1550–63.

    Article  CAS  PubMed  Google Scholar 

  81. Miao HH, Wang M, Wang HX, Tian M, Xue FS. Ginsenoside Rg1 attenuates isoflurane/surgery-induced cognitive disorders and sirtuin 3 dysfunction. Biosci Rep. 2019;39:BSR20190069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kezhu W, Pan X, Cong L, Liming D, Beiyue Z, Jingwei L, et al. Effects of ginsenoside Rg1 on learning and memory in a reward-directed instrumental conditioning task in chronic restraint stressed rats. Phytother Res. 2017;31:81–9.

    Article  PubMed  Google Scholar 

  83. Jin Y, Peng J, Wang X, Zhang D, Wang T. Ameliorative effect of ginsenoside Rg1 on lipopolysaccharide-induced cognitive impairment: Role of cholinergic system. Neurochem Res. 2017;42:1299–307.

    Article  CAS  PubMed  Google Scholar 

  84. Rasmusson AM, Pineles SL, Brown KD, Pinna G. A role for deficits in GABAergic neurosteroids and their metabolites with NMDA receptor antagonist activity in the pathophysiology of posttraumatic stress disorder. J Neuroendocrinol. 2022;34:e13062.

    Article  CAS  PubMed  Google Scholar 

  85. Raymundi AM, da Silva TR, Sohn JMB, Bertoglio LJ, Stern CA. Effects of (9)-tetrahydrocannabinol on aversive memories and anxiety: A review from human studies. BMC Psychiatry. 2020;20:420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang J, Gao F, Cui S, Yang S, Gao F, Wang X, et al. Utility of 7,8-dihydroxyflavone in preventing astrocytic and synaptic deficits in the hippocampus elicited by ptsd. Pharmacol Res. 2022;176:106079.

    Article  CAS  PubMed  Google Scholar 

  87. Gaubert F, Chainay H. Decision-making competence in patients with Alzheimer’s disease: A review of the literature. Neuropsychol Rev. 2021;31:267–87.

    Article  PubMed  Google Scholar 

  88. Robbins M, Clayton E, Kaminski, Schierle GS. Synaptic tau: A pathological or physiological phenomenon? Acta Neuropathol Commun. 2021;9:149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zhu G, Wang Y, Li J, Wang J. Chronic treatment with ginsenoside Rg1 promotes memory and hippocampal long-term potentiation in middle-aged mice. Neuroscience. 2015;292:81–9.

    Article  CAS  PubMed  Google Scholar 

  90. Yang X, Chu SF, Wang ZZ, Li FF, Yuan YH, Chen NH. Ginsenoside Rg1 exerts neuroprotective effects in 3-nitropronpionic acid-induced mouse model of Huntington’s disease via suppressing MAPKs and NF-kappaB pathways in the striatum. Acta Pharmacol Sin. 2021;42:1409–21.

    Article  CAS  PubMed  Google Scholar 

  91. Gao Y, Li J, Wang J, Li X, Li J, Chu S, et al. Ginsenoside Rg1 prevent and treat inflammatory diseases: A review. Int Immunopharmacol. 2020;87:106805.

    Article  CAS  PubMed  Google Scholar 

  92. Cheng Y, Shen LH, Zhang JT. Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. Acta Pharmacol Sin. 2005;26:143–9.

    Article  CAS  PubMed  Google Scholar 

  93. Shih YH, Tu LH, Chang TY, Ganesan K, Chang WW, Chang PS, et al. Tdp-43 interacts with amyloid-beta, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease. Nat Commun. 2020;11:5950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Montalbano M, McAllen S, Cascio FL, Sengupta U, Garcia S, Bhatt N, et al. Tdp-43 and tau oligomers in Alzheimer’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Neurobiol Dis. 2020;146:105130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Meneses A, Koga S, O’Leary J, Dickson DW, Bu G, Zhao N. Tdp-43 pathology in Alzheimer’s disease. Mol Neurodegener. 2021;16:84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Josephs KA, Whitwell JL, Tosakulwong N, Weigand SD, Murray ME, Liesinger AM, et al. Tar DNA-binding protein 43 and pathological subtype of Alzheimer’s disease impact clinical features. Ann Neurol. 2015;78:697–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nag S, Yu L, Boyle PA, Leurgans SE, Bennett DA, Schneider JA. Tdp-43 pathology in anterior temporal pole cortex in aging and Alzheimer’s disease. Acta Neuropathol Commun. 2018;6:33.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Lin M, Sun W, Gong W, Ding Y, Zhuang Y, Hou Q. Ginsenoside Rg1 protects against transient focal cerebral ischemic injury and suppresses its systemic metabolic changes in cerabral injury rats. Acta Pharm Sin B. 2015;5:277–84.

    Article  PubMed  PubMed Central  Google Scholar 

  99. He C, Feng R, Sun Y, Chu S, Chen J, Ma C, et al. Simultaneous quantification of ginsenoside Rg1 and its metabolites by HPLC-MS/MS: Rg1 excretion in rat bile, urine and feces. Acta Pharm Sin B. 2016;6:593–9.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Shen J, Zhao Z, Shang W, Liu C, Zhang B, Zhao L, et al. Ginsenoside Rg1 nanoparticle penetrating the blood-brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction. Int J Nanomed. 2017;12:6477–86.

    Article  CAS  Google Scholar 

  101. Liang W, Xu W, Zhu J, Zhu Y, Gu Q, Li Y, et al. Ginkgo biloba extract improves brain uptake of ginsenosides by increasing blood-brain barrier permeability via activating A1 adenosine receptor signaling pathway. J Ethnopharmacol. 2020;246:112243.

    Article  CAS  PubMed  Google Scholar 

  102. Baek JS, Yeon WG, Lee CA, Hwang SJ, Park JS, Kim DC, et al. Preparation and characterization of mucoadhesive enteric-coating ginsenoside-loaded microparticles. Arch Pharm Res. 2015;38:761–8.

    Article  CAS  PubMed  Google Scholar 

  103. Park SJ, Lim KH, Noh JH, Jeong EJ, Kim YS, Han BC, et al. Subacute oral toxicity study of korean red ginseng extract in sprague-dawley rats. Toxicol Res. 2013;29:285–92.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Zhai K, Duan H, Wang W, Zhao S, Khan GJ, Wang M, et al. Ginsenoside Rg1 ameliorates blood-brain barrier disruption and traumatic brain injury via attenuating macrophages derived exosomes miR-21 release. Acta Pharm Sin B. 2021;11:3493–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Martinelli C, Pucci C, Battaglini M, Marino A, Ciofani G. Antioxidants and nanotechnology: Promises and limits of potentially disruptive approaches in the treatment of central nervous system diseases. Adv Health Mater. 2020;9:e1901589.

    Article  Google Scholar 

  106. Liu J, Nile SH, Xu G, Wang Y, Kai G. Systematic exploration of Astragalus membranaceus and Panax ginseng as immune regulators: Insights from the comparative biological and computational analysis. Phytomedicine. 2021;86:153077.

    Article  CAS  PubMed  Google Scholar 

  107. Olaleye OE, Niu W, Du FF, Wang FQ, Xu F, Pintusophon S, et al. Multiple circulating saponins from intravenous ShenMai inhibit OATP1Bs in vitro: Potential joint precipitants of drug interactions. Acta Pharmacol Sin. 2019;40:833–49.

    Article  CAS  PubMed  Google Scholar 

  108. Yang X, Wang L, Zhang Z, Hu J, Liu X, Wen H, et al. Ginsenoside Rb1 enhances plaque stability and inhibits adventitial vasa vasorum via the modulation of miR-33 and PEDF. Front Cardiovasc Med. 2021;8:654670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wang M, Wang R, Sun H, Sun G, Sun X. Ginsenoside Rb1 ameliorates cardiotoxicity triggered by aconitine via inhibiting calcium overload and pyroptosis. Phytomedicine. 2021;83:153468.

    Article  CAS  PubMed  Google Scholar 

  110. Jiang L, Yin X, Chen YH, Chen Y, Jiang W, Zheng H, et al. Proteomic analysis reveals ginsenoside Rb1 attenuates myocardial ischemia/reperfusion injury through inhibiting ROS production from mitochondrial complex I. Theranostics. 2021;11:1703–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yu S, Xia H, Guo Y, Qian X, Zou X, Yang H, et al. Ginsenoside Rb1 retards aging process by regulating cell cycle, apoptotic pathway and metabolism of aging mice. J Ethnopharmacol. 2020;255:112746.

    Article  CAS  PubMed  Google Scholar 

  112. Yang X, Dong B, An L, Zhang Q, Chen Y, Wang H, et al. Ginsenoside Rb1 ameliorates glycemic disorder in mice with high fat diet-induced obesity via regulating gut microbiota and amino acid metabolism. Front Pharmacol. 2021;12:756491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Jiang N, Huang H, Zhang Y, Lv J, Wang Q, He Q, et al. Ginsenoside Rb1 produces antidepressant-like effects in a chronic social defeat stress model of depression through the BDNF-Trkb signaling pathway. Front Pharmacol. 2021;12:680903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lai Y, Tan Q, Xv S, Huang S, Wang Y, Li Y, et al. Ginsenoside Rb1 alleviates alcohol-induced liver injury by inhibiting steatosis, oxidative stress, and inflammation. Front Pharmacol. 2021;12:616409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chen H, Shen J, Li H, Zheng X, Kang D, Xu Y, et al. Ginsenoside Rb1 exerts neuroprotective effects through regulation of lactobacillus helveticus abundance and GABAA receptor expression. J Ginseng Res. 2020;44:86–95.

    Article  PubMed  Google Scholar 

  116. Li DW, Zhou FZ, Sun XC, Li SC, Yang JB, Sun HH, et al. Ginsenoside Rb1 protects dopaminergic neurons from inflammatory injury induced by intranigral lipopolysaccharide injection. Neural Regen Res. 2019;14:1814–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Shi YH, Li Y, Wang Y, Xu Z, Fu H, Zheng GQ. Ginsenoside-Rb1 for ischemic stroke: A systematic review and meta-analysis of preclinical evidence and possible mechanisms. Front Pharmacol. 2020;11:285.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Zuo X, Li Q, Ya F, Ma LJ, Tian Z, Zhao M, et al. Ginsenosides Rb2 and Rd2 isolated from panax notoginseng flowers attenuate platelet function through P2Y12-mediated cAMP/PKA and PI3K/AKT/ERK1/2 signaling. Food Funct. 2021;12:5793–805.

    Article  CAS  PubMed  Google Scholar 

  119. Choi RJ, Mohamad Zobir SZ, Alexander-Dann B, Sharma N, Ma MKL, Lam BYH, et al. Combination of ginsenosides Rb2 and Rg3 promotes angiogenic phenotype of human endothelial cells via PI3K/AKT and MAPK/ERK pathways. Front Pharmacol. 2021;12:618773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kim DH, Kim DW, Jung BH, Lee JH, Lee H, Hwang GS, et al. Ginsenoside Rb2 suppresses the glutamate-mediated oxidative stress and neuronal cell death in HT22 cells. J Ginseng Res. 2019;43:326–34.

    Article  PubMed  Google Scholar 

  121. Phi LTH, Wijaya YT, Sari IN, Yang YG, Lee YK, Kwon HY. The anti-metastatic effect of ginsenoside Rb2 in colorectal cancer in an EGFR/SOX2-dependent manner. Cancer Med. 2018;7:5621–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Huang Q, Wang T, Wang HY. Ginsenoside Rb2 enhances the anti-inflammatory effect of omega-3 fatty acid in LPS-stimulated RAW264.7 macrophages by upregulating GPR120 expression. Acta Pharmacol Sin. 2017;38:192–200.

    Article  CAS  PubMed  Google Scholar 

  123. Dai S, Hong Y, Xu J, Lin Y, Si Q, Gu X. Ginsenoside Rb2 promotes glucose metabolism and attenuates fat accumulation via AKT-dependent mechanisms. Biomed Pharmacother. 2018;100:93–100.

    Article  CAS  PubMed  Google Scholar 

  124. Li H, Cui L, Liu Q, Dou S, Wang W, Xie M, et al. Ginsenoside Rb3 alleviates CSE-induced TROP2 upregulation through p38 MAPK and NF-kappaB pathways in basal cells. Am J Respir Cell Mol Biol. 2021;64:747–59.

    Article  CAS  PubMed  Google Scholar 

  125. Xing JJ, Hou JG, Ma ZN, Wang Z, Ren S, Wang YP, et al. Ginsenoside Rb3 provides protective effects against cisplatininduced nephrotoxicity via regulation of AMPK-/mTOR-mediated autophagy and inhibition of apoptosis in vitro and in vivo. Cell Prolif. 2019;52:e12627.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Zhang Y, Ji H, Qiao O, Li Z, Pecoraro L, Zhang X, et al. Nanoparticle conjugation of ginsenoside Rb3 inhibits myocardial fibrosis by regulating pparalpha pathway. Biomed Pharmacother. 2021;139:111630.

    Article  CAS  PubMed  Google Scholar 

  127. Yu T, Yang Y, Kwak YS, Song GG, Kim MY, Rhee MH, et al. Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2. J Ginseng Res. 2017;41:127–33.

    Article  PubMed  Google Scholar 

  128. Huang Q, Su H, Qi B, Wang Y, Yan K, Wang X, et al. A SIRT1 activator, ginsenoside Rc, promotes energy metabolism in cardiomyocytes and neurons. J Am Chem Soc. 2021;143:1416–27.

    Article  CAS  PubMed  Google Scholar 

  129. Yang B, Wang R, Ji LL, Li XP, Li XH, Zhou HG, et al. Exploration of the function of ginsenoside Rd attenuates lipopolysaccharide-induced lung injury: A study of network pharmacology and experimental validation. Shock. 2022;57:212–20.

    Article  CAS  PubMed  Google Scholar 

  130. Ren K, Li S, Ding J, Zhao S, Liang S, Cao X, et al. Ginsenoside Rd attenuates mouse experimental autoimmune neuritis by modulating monocyte subsets conversion. Biomed Pharmacother. 2021;138:111489.

    Article  CAS  PubMed  Google Scholar 

  131. Zhang B, Hu X, Wang H, Wang R, Sun Z, Tan X, et al. Effects of a dammarane-type saponin, ginsenoside Rd, in nicotine-induced vascular endothelial injury. Phytomedicine. 2020;79:153325.

    Article  CAS  PubMed  Google Scholar 

  132. Chen XM, Ji SF, Liu YH, Xue XM, Xu J, Gu ZH, et al. Ginsenoside Rd ameliorates auditory cortex injury associated with military aviation noise-induced hearing loss by activating SIRT1/PGC-1alpha signaling pathway. Front Physiol. 2020;11:788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Han SK, Joo MK, Kim JK, Jeung W, Kang H, Kim DH. Bifidobacteria-fermented red ginseng and its constituents ginsenoside rd and protopanaxatriol alleviate anxiety/depression in mice by the amelioration of gut dysbiosis. Nutrients. 2020;12:901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Yao L, Han Z, Zhao G, Xiao Y, Zhou X, Dai R, et al. Ginsenoside Rd ameliorates high fat diet-induced obesity by enhancing adaptive thermogenesis in a cAMP-dependent manner. Obesity (Silver Spring). 2020;28:783–92.

    Article  CAS  PubMed  Google Scholar 

  135. Gao C, Zhang K, Liang F, Ma W, Jiang X, Wang H, et al. Inhibition of the Ras/ERK1/2 pathway contributes to the protective effect of ginsenoside Re against intimal hyperplasia. Food Funct. 2021;12:6755–65.

    Article  CAS  PubMed  Google Scholar 

  136. Wang H, Lv J, Jiang N, Huang H, Wang Q, Liu X. Ginsenoside Re protects against chronic restraint stress-induced cognitive deficits through regulation of NLRP3 and Nrf2 pathways in mice. Phytother Res. 2021. https://doi.org/10.1002/ptr.6947.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Sun H, Ling S, Zhao D, Li J, Li Y, Qu H, et al. Ginsenoside Re treatment attenuates myocardial hypoxia/reoxygenation injury by inhibiting HIF-1alpha ubiquitination. Front Pharmacol. 2020;11:532041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kim JM, Park CH, Park SK, Seung TW, Kang JY, Ha JS, et al. Ginsenoside Re ameliorates brain insulin resistance and cognitive dysfunction in high fat diet-induced C57BL/6 mice. J Agric Food Chem. 2017;65:2719–29.

    Article  CAS  PubMed  Google Scholar 

  139. Lee HR, Jung JM, Seo JY, Chang SE, Song Y. Anti-melanogenic property of ginsenoside Rf from panax ginseng via inhibition of CREB/MITF pathway in melanocytes and ex vivo human skin. J Ginseng Res. 2021;45:555–64.

    Article  PubMed  Google Scholar 

  140. Kim Y, Lee HY, Choi YJ, Cho SH. Antidepressant effects of ginsenoside Rf on behavioral change in the glial degeneration model of depression by reversing glial loss. J Ginseng Res. 2020;44:603–10.

    Article  PubMed  Google Scholar 

  141. Song H, Park J, Choi K, Lee J, Chen J, Park HJ, et al. Ginsenoside Rf inhibits cyclooxygenase-2 induction via peroxisome proliferator-activated receptor gamma in A549 cells. J Ginseng Res. 2019;43:319–25.

    Article  PubMed  Google Scholar 

  142. Kim MK, Kang H, Baek CW, Jung YH, Woo YC, Choi GJ, et al. Antinociceptive and anti-inflammatory effects of ginsenoside Rf in a rat model of incisional pain. J Ginseng Res. 2018;42:183–91.

    Article  PubMed  Google Scholar 

  143. Lu ML, Wang J, Sun Y, Li C, Sun TR, Hou XW, et al. Ginsenoside Rg1 attenuates mechanical stress-induced cardiac injury via calcium sensing receptor-related pathway. J Ginseng Res. 2021;45:683–94.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Jin J, Zhong Y, Long J, Wu T, Jiang Q, Wang H, et al. Ginsenoside Rg1 relieves experimental colitis by regulating balanced differentiation of Tfh/Treg cells. Int Immunopharmacol. 2021;100:108133.

    Article  CAS  PubMed  Google Scholar 

  145. Wang Z, Wang L, Jiang R, Li C, Chen X, Xiao H, et al. Ginsenoside Rg1 prevents bone marrow mesenchymal stem cell senescence via Nrf2 and PI3K/AKT signaling. Free Radic Biol Med. 2021;174:182–94.

    Article  CAS  PubMed  Google Scholar 

  146. Xu X, Qu Z, Qian H, Li Z, Sun X, Zhao X, et al. Ginsenoside Rg1 ameliorates reproductive function injury in C57BL/6J mice induced by di-N-butyl-phthalate. Environ Toxicol. 2021;36:789–99.

    Article  CAS  PubMed  Google Scholar 

  147. Huang L, Peng Z, Lu C, Chen Y, Lv JW, Qin M, et al. Ginsenoside Rg1 alleviates repeated alcohol exposure-induced psychomotor and cognitive deficits. Chin Med. 2020;15:44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Liu JQ, Zhao M, Zhang Z, Cui LY, Zhou X, Zhang W, et al. Rg1 improves lps-induced parkinsonian symptoms in mice via inhibition of NF-kappab signaling and modulation of M1/M2 polarization. Acta Pharmacol Sin. 2020;41:523–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Shen X, Dong X, Han Y, Li Y, Ding S, Zhang H, et al. Ginsenoside Rg1 ameliorates glomerular fibrosis during kidney aging by inhibiting NOX4 and NLRP3 inflammasome activation in SAMP8 mice. Int Immunopharmacol. 2020;82:106339.

    Article  CAS  PubMed  Google Scholar 

  150. Xu YP, Cui XY, Liu YT, Cui SY, Zhang YH. Ginsenoside Rg1 promotes sleep in rats by modulating the noradrenergic system in the locus coeruleus and serotonergic system in the dorsal raphe nucleus. Biomed Pharmacother. 2019;116:109009.

    Article  CAS  PubMed  Google Scholar 

  151. Liu Q, Zhang FG, Zhang WS, Pan A, Yang YL, Liu JF, et al. Ginsenoside Rg1 inhibits glucagon-induced hepatic gluconeogenesis through Akt-FoxO1 interaction. Theranostics. 2017;7:4001–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Lin J, Huang HF, Yang SK, Duan J, Qu SM, Yuan B, et al. The effect of ginsenoside Rg1 in hepatic ischemia reperfusion (I/R) injury ameliorates ischemia-reperfusion-induced liver injury by inhibiting apoptosis. Biomed Pharmacother. 2020;129:110398.

    Article  CAS  PubMed  Google Scholar 

  153. Jeon H, Huynh DTN, Baek N, Nguyen TLL, Heo KS. Ginsenoside-Rg2 affects cell growth via regulating ROS-mediated AMPK activation and cell cycle in MCF-7 cells. Phytomedicine. 2021;85:153549.

    Article  CAS  PubMed  Google Scholar 

  154. Cui J, Shan R, Cao Y, Zhou Y, Liu C, Fan Y. Protective effects of ginsenoside Rg2 against memory impairment and neuronal death induced by Abeta25-35 in rats. J Ethnopharmacol. 2021;266:113466.

    Article  CAS  PubMed  Google Scholar 

  155. Gou D, Pei X, Wang J, Wang Y, Hu C, Song C, et al. Antiarrhythmic effects of ginsenoside Rg2 on calcium chloride-induced arrhythmias without oral toxicity. J Ginseng Res. 2020;44:717–24.

    Article  PubMed  Google Scholar 

  156. Cheng B, Gao W, Wu X, Zheng M, Yu Y, Song C, et al. Ginsenoside Rg2 ameliorates high-fat diet-induced metabolic disease through Sirt1. J Agric Food Chem. 2020;68:4215–26.

    Article  CAS  PubMed  Google Scholar 

  157. Lai Q, Liu FM, Rao WL, Yuan GY, Fan ZY, Zhang L, et al. Aminoacylase-1 plays a key role in myocardial fibrosis and the therapeutic effects of 20(S)-ginsenoside Rg3 in mouse heart failure. Acta Pharmacol Sin. 2022;43:2003–15.

    Article  CAS  PubMed  Google Scholar 

  158. Han NR, Ko SG, Moon PD, Park HJ. Ginsenoside Rg3 attenuates skin disorders via down-regulation of MDM2/HIF1alpha signaling pathway. J Ginseng Res. 2021;45:610–6.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Song M, Cui Y, Wang Q, Zhang X, Zhang J, Liu M, et al. Ginsenoside Rg3 alleviates aluminum chloride-induced bone impairment in rats by activating the TGF-beta1/Smad signaling pathway. J Agric Food Chem. 2021;69:12634–44.

    Article  CAS  PubMed  Google Scholar 

  160. Kim D, Yang KE, Kim DW, Hwang HY, Kim J, Choi JS, et al. Activation of Ca2+-ampk-mediated autophagy by ginsenoside Rg3 attenuates cellular senescence in human dermal fibroblasts. Clin Transl Med. 2021;11:e521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Nakhjavani M, Smith E, Yeo K, Palethorpe HM, Tomita Y, Price TJ, et al. Anti-angiogenic properties of ginsenoside Rg3 epimers: In vitro assessment of single and combination treatments. Cancers (Basel). 2021;13:2223.

    Article  CAS  PubMed  Google Scholar 

  162. Geng J, Fu W, Yu X, Lu Z, Liu Y, Sun M, et al. Ginsenoside Rg3 alleviates ox-LDL induced endothelial dysfunction and prevents atherosclerosis in ApoE-/- mice by regulating PPARgamma/FAK signaling pathway. Front Pharmacol. 2020;11:500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Shi Y, Wang H, Zheng M, Xu W, Yang Y, Shi F. Ginsenoside Rg3 suppresses the NLRP3 inflammasome activation through inhibition of its assembly. FASEB J. 2020;34:208–21.

    Article  CAS  PubMed  Google Scholar 

  164. Ren Z, Chen X, Hong L, Zhao X, Cui G, Li A, et al. Nanoparticle conjugation of ginsenoside Rg3 inhibits hepatocellular carcinoma development and metastasis. Small. 2020;16:e1905233.

    Article  PubMed  Google Scholar 

  165. Zhang K, Liu Y, Wang C, Li J, Xiong L, Wang Z, et al. Evaluation of the gastroprotective effects of 20 (S)-ginsenoside Rg3 on gastric ulcer models in mice. J Ginseng Res. 2019;43:550–61.

    Article  PubMed  Google Scholar 

  166. Su WY, Li Y, Chen X, Li X, Wei H, Liu Z, et al. Ginsenoside Rh1 improves type 2 diabetic nephropathy through AMPK/PI3K/AKT-mediated inflammation and apoptosis signaling pathway. Am J Chin Med. 2021;49:1215–33.

    Article  CAS  PubMed  Google Scholar 

  167. Lu C, Shi Z, Dong L, Lv J, Xu P, Li Y, et al. Exploring the effect of ginsenoside Rh1 in a sleep deprivation-induced mouse memory impairment model. Phytother Res. 2017;31:763–70.

    Article  CAS  PubMed  Google Scholar 

  168. Chen C, Wang YS, Zhang ET, Li GA, Liu WY, Li Y, et al. (20S) ginsenoside Rh2 exerts its anti-tumor effect by disrupting the HSP90A-Cdc37 system in human liver cancer cells. Int J Mol Sci. 2021;22:13170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Chen XY, Qian F, Wang YY, Liu Y, Sun Y, Zha WB, et al. Ginsenoside 20(S)-Rh2 promotes cellular pharmacokinetics and intracellular antibacterial activity of levofloxacin against staphylococcus aureus through drug efflux inhibition and subcellular stabilization. Acta Pharmacol Sin. 2021;42:1930–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Chen X, Xu T, Lv X, Zhang J, Liu S. Ginsenoside Rh2 alleviates ulcerative colitis by regulating the STAT3/miR-214 signaling pathway. J Ethnopharmacol. 2021;274:113997.

    Article  CAS  PubMed  Google Scholar 

  171. Lv J, Lu C, Jiang N, Wang H, Huang H, Chen Y, et al. Protective effect of ginsenoside Rh2 on scopolamine-induced memory deficits through regulation of cholinergic transmission, oxidative stress and the ERK-CREB-BDNF signaling pathway. Phytother Res. 2021;35:337–45.

    Article  CAS  PubMed  Google Scholar 

  172. Xia T, Zhang B, Li Y, Fang B, Zhu X, Xu B, et al. New insight into 20(S)-ginsenoside Rh2 against t-cell acute lymphoblastic leukemia associated with the gut microbiota and the immune system. Eur J Med Chem. 2020;203:112582.

    Article  CAS  PubMed  Google Scholar 

  173. Hsieh YH, Deng JS, Chang YS, Huang GJ. Ginsenoside Rh2 ameliorates lipopolysaccharide-induced acute lung injury by regulating the TLR4/PI3K/AKT/mTOR, Raf-1/MEK/ERK, and Keap1/Nrf2/Ho-1 signaling pathways in mice. Nutrients. 2018;10:1208.

    Article  PubMed  PubMed Central  Google Scholar 

  174. Kang S, Im K, Kim G, Min H. Antiviral activity of 20(R)-ginsenoside Rh2 against murine gammaherpesvirus. J Ginseng Res. 2017;41:496–502.

    Article  CAS  PubMed  Google Scholar 

  175. Lee YY, Park JS, Lee EJ, Lee SY, Kim DH, Kang JL, et al. Anti-inflammatory mechanism of ginseng saponin metabolite Rh3 in lipopolysaccharide-stimulated microglia: critical role of 5’-adenosine monophosphate-activated protein kinase signaling pathway. J Agric Food Chem. 2015;63:3472–80.

    Article  CAS  PubMed  Google Scholar 

  176. Lee HL, Kang KS. Protective effect of ginsenoside Rh3 against anticancer drug-induced apoptosis in LLC-PK1 kidney cells. J Ginseng Res. 2017;41:227–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Felger JC. Imaging the role of inflammation in mood and anxiety-related disorders. Curr Neuropharmacol. 2018;16:533–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Price RB, Duman R. Neuroplasticity in cognitive and psychological mechanisms of depression: An integrative model. Mol Psychiatry. 2020;25:530–43.

    Article  PubMed  Google Scholar 

  179. Li M, Li C, Yu H, Cai X, Shen X, Sun X, et al. Lentivirus-mediated interleukin-1beta (IL-1beta) knock-down in the hippocampus alleviates lipopolysaccharide (LPS)-induced memory deficits and anxiety- and depression-like behaviors in mice. J Neuroinflammation. 2017;14:190.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Palmfeldt J, Henningsen K, Eriksen SA, Muller HK, Wiborg O. Protein biomarkers of susceptibility and resilience to stress in a rat model of depression. Mol Cell Neurosci. 2016;74:87–95.

    Article  CAS  PubMed  Google Scholar 

  181. Bradburn S, Murgatroyd C, Ray N. Neuroinflammation in mild cognitive impairment and Alzheimer’s disease: A meta-analysis. Ageing Res Rev. 2019;50:1–8.

    Article  CAS  PubMed  Google Scholar 

  182. Chandra A, Dervenoulas G, Politis M. Alzheimer’s disease neuroimaging I. Magnetic resonance imaging in Alzheimer’s disease and mild cognitive impairment. J Neurol. 2019;266:1293–302.

    Article  PubMed  Google Scholar 

  183. Lopez-Ortiz S, Pinto-Fraga J, Valenzuela PL, Martin-Hernandez J, Seisdedos MM, Garcia-Lopez O, et al. Physical exercise and Alzheimer’s disease: Effects on pathophysiological molecular pathways of the disease. Int J Mol Sci. 2021;22.

  184. Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior. Biol Psychiatry. 2018;83:38–49.

    Article  CAS  PubMed  Google Scholar 

  185. Li Y, Fan C, Wang L, Lan T, Gao R, Wang W, et al. Microrna-26a-3p rescues depression-like behaviors in male rats via preventing hippocampal neuronal anomalies. J Clin Invest. 2021;131.

  186. Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017;4:409–18.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Kamat PK, Kalani A, Rai S, Swarnkar S, Tota S, Nath C, et al. Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: Understanding the therapeutics strategies. Mol Neurobiol. 2016;53:648–61.

    Article  CAS  PubMed  Google Scholar 

  188. Sharma VK, Singh TG, Singh S, Garg N, Dhiman S. Apoptotic pathways and Alzheimer’s disease: Probing therapeutic potential. Neurochem Res. 2021;46:3103–22.

    Article  CAS  PubMed  Google Scholar 

  189. Tank R, Ward J, Flegal KE, Smith DJ, Bailey MES, Cavanagh J, et al. Association between polygenic risk for Alzheimer’s disease, brain structure and cognitive abilities in uk biobank. Neuropsychopharmacology. 2022;47:564–9.

    Article  CAS  PubMed  Google Scholar 

  190. Gbyl K, Rostrup E, Raghava JM, Andersen C, Rosenberg R, Larsson HBW, et al. Volume of hippocampal subregions and clinical improvement following electroconvulsive therapy in patients with depression. Prog Neuropsychopharmacol Biol Psychiatry. 2021;104:110048.

    Article  PubMed  Google Scholar 

  191. Chakraborty S, Tripathi SJ, Srikumar BN, Raju TR, Shankaranarayana, Rao BS. Chronic brain stimulation rewarding experience ameliorates depression-induced cognitive deficits and restores aberrant plasticity in the prefrontal cortex. Brain Stimul. 2019;12:752–66.

    Article  PubMed  Google Scholar 

  192. Li A, Li F, Elahifasaee F, Liu M, Zhang L. Alzheimer’s Disease Neuroimaging Initiative. Hippocampal shape and asymmetry analysis by cascaded convolutional neural networks for Alzheimer’s disease diagnosis. Brain Imaging Behav. 2021;15:2330–9.

    Article  PubMed  Google Scholar 

  193. Kabir MT, Uddin MS, Mamun AA, Jeandet P, Aleya L, Mansouri RA, et al. Combination drug therapy for the management of Alzheimer’s disease. Int J Mol Sci. 2020;21.

  194. Zhong SJ, Wang L, Gu RZ, Zhang WH, Lan R, Qin XY. Ginsenoside Rg1 ameliorates the cognitive deficits in D-galactose and AlCl3-induced aging mice by restoring FGF2-Akt and BDNF-TrkB signaling axis to inhibit apoptosis. Int J Med Sci. 2020;17:1048–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Nie L, Xia J, Li H, Zhang Z, Yang Y, Huang X, et al. Ginsenoside Rg1 ameliorates behavioral abnormalities and modulates the hippocampal proteomic change in triple transgenic mice of Alzheimer’s disease. Oxid Med Cell Longev. 2017;2017:6473506.

    Article  PubMed  PubMed Central  Google Scholar 

  196. Yang Y, Wang L, Zhang C, Guo Y, Li J, Wu C, et al. Ginsenoside Rg1 improves Alzheimer’s disease by regulating oxidative stress, apoptosis, and neuroinflammation through Wnt/GSK-3beta/beta-catenin signaling pathway. Chem Biol Drug Des. 2022;99:884–96.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Natural Science Foundation of China (81673716, 82004481), Anhui Natural Science Foundation (2208085MH282), University Excellent Top Talent Cultivation Foundation of Anhui Province (gxgnfx2020089) and Key Research and Development Plan of Anhui Province (202104j07020004).

Author information

Authors and Affiliations

  1. Key Laboratory of Xin’an Medicine, the Ministry of Education and Key Laboratory of Molecular Biology (Brain diseases), Anhui University of Chinese Medicine, Hefei, 230012, China

    Shao-jie Yang, Ping Cheng, Li-xia Chen, Jia-min Hu & Guo-qi Zhu

  2. The Second Affiliation Hospital of Anhui University of Chinese Medicine, Hefei, 230061, China

    Jing-ji Wang

Authors
  1. Shao-jie Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing-ji Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ping Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li-xia Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia-min Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guo-qi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jing-ji Wang or Guo-qi Zhu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Sj., Wang, Jj., Cheng, P. et al. Ginsenoside Rg1 in neurological diseases: From bench to bedside. Acta Pharmacol Sin 44, 913–930 (2023). https://doi.org/10.1038/s41401-022-01022-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-022-01022-1

Keywords

Search

Advanced search

Quick links