Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Effects of Red ginseng on neuroinflammation in neurodegenerative diseases

  • Min Yeong Lee (Department of Chemistry & Life Science, Sahmyook University) ;
  • Mikyung Kim (Department of Chemistry & Life Science, Sahmyook University)
  • Received : 2023.03.29
  • Accepted : 2023.08.25
  • Published : 2024.01.01
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Abstract

Red ginseng (RG) is widely used as a herbal medicine. As the human lifespan has increased, numerous diseases have developed, and RG has also been used to treat various diseases. Neurodegenerative diseases are major problems that modern people face through their lives. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are featured by progressive nerve system damage. Recently, neuroinflammation has emerged as a degenerative factor and is an immune response in which cytokines with nerve cells that constitute the nervous system. RG, a natural herbal medicine with fewer side effects than chemically synthesized drugs, is currently in the spotlight. Therefore, we reviewed studies reporting the roles of RG in treating neuroinflammation and neurodegenerative diseases and found that RG might help alleviate neurodegenerative diseases by regulating neuroinflammation.

Keywords

Acknowledgement

This research was supported by the National Research Foundation (NRF) of Korea (NRF-2021R1G1A1093620).

References

  1. Pahwa R, Goyal A, Jialal I. Chronic inflammation. 2022.
  2. Austin PJ, Moalem-Taylor G. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol 2010;229:26-50. https://doi.org/10.1016/j.jneuroim.2010.08.013.
  3. Shih RH, Wang CY, Yang CM. NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 2015;8. https://doi.org/10.3389/fnmol.2015.00077.
  4. Ahmed S, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: pivotal roles in inflammation. Biochimica et Biophysica Acta (BBA) - Mol Basis Dis 2017;1863:585-97. https://doi.org/10.1016/j.bbadis.2016.11.005.
  5. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860-7. https://doi.org/10.1038/nature01322.
  6. Chow YY, Chin KY. The role of inflammation in the pathogenesis of osteoarthritis. Mediators Inflamm 2020;2020:1-19. https://doi.org/10.1155/2020/8293921.
  7. Zipp F, Aktas O. The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci 2006;29:518-27. https://doi.org/10.1016/j.tins.2006.07.006.
  8. Pizza V, Agresta A, D'Acunto C W, Festa M, Capasso A. Neuroinflamm-aging and neurodegenerative diseases: an overview. CNS Neurol Disord Drug Targets 2011;10:621-34. https://doi.org/10.2174/187152711796235014.
  9. Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases (Review). Mol Med Rep 2016;13:3391-6. https://doi.org/10.3892/mmr.2016.4948.
  10. Calcia MA, Bonsall DR, Bloomfield PS, Selvaraj S, Barichello T, Howes OD. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology (Berl) 2016;233:1637-50. https://doi.org/10.1007/s00213-016-4218-9.
  11. Krasnova IN, Justinova Z, Cadet JL. Methamphetamine addiction: involvement of CREB and neuroinflammatory signaling pathways. Psychopharmacology (Berl) 2016;233:1945-62. https://doi.org/10.1007/s00213-016-4235-8.
  12. Jurgens HA, Amancherla K, Johnson RW. Influenza infection induces neuroinflammation, alters hippocampal neuron morphology, and impairs cognition in adult mice. Journal of Neuroscience 2012;32:3958-68. https://doi.org/10.1523/JNEUROSCI.6389-11.2012.
  13. Matt SM, Johnson RW. Neuro-immune dysfunction during brain aging: new insights in microglial cell regulation. Curr Opin Pharmacol 2016;26:96-101. https://doi.org/10.1016/j.coph.2015.10.009.
  14. Floyd R, Hensley K. Oxidative stress in brain aging implications for therapeutics of neurodegenerative diseases. Neurobiol Aging 2002;23:795-807. https://doi.org/10.1016/S0197-4580(02)00019-2.
  15. Vonder Haar C, Ferland JN, Kaur S, Riparip L, Rosi S, Winstanley CA. Cocaine self-administration is increased after frontal traumatic brain injury and associated with neuroinflammation. Europ J Neurosci 2019;50:2134-45. https://doi.org/10.1111/ejn.14123.
  16. Kim DY, Hao J, Liu R, Turner G, Shi FD, Rho JM. Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis. PLoS One 2012;7:e35476. https://doi.org/10.1371/journal.pone.0035476.
  17. Elewa HF, Hilali H, Hess DC, Machado LS, Fagan SC. Minocycline for short-term neuroprotection. Pharmacotherapy 2006;26:515-21. https://doi.org/10.1592/phco.26.4.515.
  18. Gasparini L, Ongini E, Wenk G. Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease: old and new mechanisms of action. J Neurochem 2004;91:521-36. https://doi.org/10.1111/j.1471-4159.2004.02743.x.
  19. Wixey JA, Sukumar KR, Pretorius R, Lee KM, Colditz PB, Tracey Bjorkman S, et al. Ibuprofen treatment reduces the neuroinflammatory response and associated neuronal and white matter impairment in the growth restricted newborn. Front Physiol 2019;10. https://doi.org/10.3389/fphys.2019.00541.
  20. Tabet N, Feldman H. Ibuprofen for Alzheimer's disease. Cochrane Database of System Rev 2003. https://doi.org/10.1002/14651858.cd004031.
  21. Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective. Biochem Pharmacol 2020;180:114147. https://doi.org/10.1016/j.bcp.2020.114147.
  22. Bjarnason I, Scarpignato C, Holmgren E, Olszewski M, Rainsford KD, Lanas A. Mechanisms of damage to the gastrointestinal tract from nonsteroidal anti-inflammatory drugs. Gastroenterology 2018;154:500-14. https://doi.org/10.1053/j.gastro.2017.10.049.
  23. Harirforoosh S, Waheed A, Fakhreddin J. Adverse Effects of Nonsteroidal Antiinflammatory Drugs An Update of Gastrointestinal, Cardiovascular and Renal Complications. Journal of Pharmacy & Pharmaceutical Sciences 2013;16(5):821-47.
  24. Ghasemian M, Owlia S, Owlia MB. Review of anti-inflammatory herbal medicines. Adv Pharmacol Sci 2016;2016:1-11. https://doi.org/10.1155/2016/9130979.
  25. Yatoo M, Gopalakrishnan A, Saxena A, Parray OR, Tufani NA, Chakraborty S, et al. Anti-Inflammatory Drugs and Herbs with Special Emphasis on Herbal Medicines for Countering Inflammatory Diseases and Disorders - A Review. Recent Pat Inflamm Allergy Drug Discov 2018;12:39-58. https://doi.org/10.2174/1872213X12666180115153635.
  26. David K, Traci P. Panax ginseng -. American Family Physician 2003;68(8):1539-42.
  27. Nam KY. The comparative understanding between red ginseng and white ginsengs, processed ginsengs (Panax ginseng. J Ginseng Res 2005;29:1-18. https://doi.org/10.5142/JGR.2005.29.1.001.
  28. Jung JS, Shin JA, Park EM, Lee JE, Kang YS, Min SW, et al. Anti-inflammatory mechanism of ginsenoside Rh1 in lipopolysaccharide-stimulated microglia: critical role of the protein kinase A pathway and hemeoxygenase-1 expression. J Neurochem 2010;115:1668-80. https://doi.org/10.1111/j.1471-4159.2010.07075.x.
  29. 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-3β/β-catenin signaling pathway. Chem Biol Drug Des 2022;99:884-96. https://doi.org/10.1111/cbdd.14041.
  30. Heng Y, Zhang QS, Mu Z, Hu JF, Yuan YH, Chen NH. 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 2016;243:7-21. https://doi.org/10.1016/j.toxlet.2015.12.005.
  31. Tachikawa E, Kudo K, Harada K, Kashimoto T, Miyate Y, Kakizaki A, et al. Effects of ginseng saponins on responses induced by various receptor stimuli, vol. 369; 1999.
  32. Kim SN, Ha YW, Shin H, Son SH, Wu SJ, Kim YS. Simultaneous quantification of 14 ginsenosides in Panax ginseng C.A. Meyer (Korean red ginseng) by HPLC-ELSD and its application to quality control. J Pharm Biomed Anal 2007;45:164-70. https://doi.org/10.1016/j.jpba.2007.05.001.
  33. Kim JH, Yi YS, Kim MY, Cho JY. Role of ginsenosides, the main active components of Panax ginseng , in inflammatory responses and diseases. J Ginseng Res 2017;41:435-43. https://doi.org/10.1016/j.jgr.2016.08.004.
  34. Ha YW, Lim SS, Ha IJ, Na YC, Seo JJ, Shin H, et al. Preparative isolation of four ginsenosides from Korean red ginseng (steam-treated Panax ginseng C. A. Meyer), by high-speed counter-current chromatography coupled with evaporative light scattering detection. J Chromatogr A 2007;1151:37-44. https://doi.org/10.1016/j.chroma.2007.01.038.
  35. Lee SM, Bae BS, Park HW, Ahn NG, Cho BG, Cho YL, et al. Characterization of Korean red ginseng (Panax ginseng Meyer): history, preparation method, and chemical composition. J Ginseng Res 2015;39:384-91. https://doi.org/10.1016/j.jgr.2015.04.009.
  36. Jang M, Lee MJ, Kim CS, Cho IH. Korean red ginseng extract attenuates 3-nitropropionic acid-induced Huntington's-like symptoms. Evidence-Based Complement Alternat Med 2013;2013. https://doi.org/10.1155/2013/237207.
  37. Lee S, Youn K, Jeong WS, Ho CT, Jun M. Protective effects of red ginseng oil against Aβ25-35-induced neuronal apoptosis and inflammation in PC12 cells. Int J Mol Sci 2017;18:2218. https://doi.org/10.3390/ijms18102218.
  38. Liu J, Zhao M, Zhang Z, Cui L, Zhou X, Zhang W, et al. Rg1 improves LPS-induced Parkinsonian symptoms in mice via inhibition of NF-κB signaling and modulation of M1/M2 polarization. Acta Pharmacol Sin 2020;41:523-34. https://doi.org/10.1038/s41401-020-0358-x.
  39. Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology 2010;129:154-69. https://doi.org/10.1111/j.1365-2567.2009.03225.x.
  40. Guzman-Martinez L, Maccioni RB, Andrade V, Navarrete LP, Pastor MG, Ramos-Escobar N. Neuroinflammation as a common feature of neurodegenerative disorders. Front Pharmacol 2019;10. https://doi.org/10.3389/fphar.2019.01008.
  41. McLarnon JG. Correlated inflammatory responses and neurodegeneration in peptide-injected animal models of Alzheimer's disease. Biomed Res Int 2014;2014:1-9. https://doi.org/10.1155/2014/923670.
  42. Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D. Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy. Alzheimers Res Ther 2010;2:1. https://doi.org/10.1186/alzrt24.
  43. Girard SD, Jacquet M, Baranger K, Migliorati M, Escoffier G, Bernard A, et al. Onset of hippocampus-dependent memory impairments in 5XFAD transgenic mouse model of Alzheimer's disease. Hippocampus 2014;24:762-72. https://doi.org/10.1002/hipo.22267.
  44. Wagner JM, Sichler ME, Schleicher EM, Franke TN, Irwin C, Low MJ, et al. € Analysis of motor function in the Tg4-42 mouse model of Alzheimer's disease. Front Behav Neurosci 2019;13. https://doi.org/10.3389/fnbeh.2019.00107.
  45. Craft JM, Watterson DM, van Eldik LJ. Human amyloid β-induced neuroinflammation is an early event in neurodegeneration. Glia 2006;53:484-90. https://doi.org/10.1002/glia.20306.
  46. Chu S, Gu J, Feng L, Liu J, Zhang M, Jia X, et al. Ginsenoside Rg5 improves cognitive dysfunction and beta-amyloid deposition in STZ-induced memory impaired rats via attenuating neuroinflammatory responses. Int Immunopharmacol 2014;19:317-26. https://doi.org/10.1016/j.intimp.2014.01.018.
  47. Lee S, Youn K, Jun M. Major compounds of red ginseng oil attenuate Aβ25-35-induced neuronal apoptosis and inflammation by modulating MAPK/NF-κB pathway. Food Funct 2018;9:4122-34. https://doi.org/10.1039/C8FO00795K.
  48. Yin Z, Raj D, Saiepour N, van Dam D, Brouwer N, Holtman IR, et al. Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer's disease. Neurobiol Aging 2017;55:115-22. https://doi.org/10.1016/j.neurobiolaging.2017.03.021.
  49. Sung PS, Lin PY, Liu CH, Su HC, Tsai KJ. Neuroinflammation and neurogenesis in Alzheimer's disease and potential therapeutic approaches. Int J Mol Sci 2020;21:701. https://doi.org/10.3390/ijms21030701.
  50. Park JS, Park EM, Kim DH, Jung K, Jung JS, Lee EJ, et al. Anti-inflammatory mechanism of ginseng saponins in activated microglia. J Neuroimmunol 2009;209:40-9. https://doi.org/10.1016/j.jneuroim.2009.01.020.
  51. Park SM, Choi MS, Sohn NW, Shin JW. Ginsenoside Rg3 attenuates microglia activation following systemic lipopolysaccharide treatment in mice. Biol Pharm Bull 2012;35:1546-52. https://doi.org/10.1248/bpb.b12-00393.
  52. Lee JS, Song JH, Sohn NW, Shin JW. Inhibitory effects of ginsenoside Rb1 on neuroinflammation following systemic lipopolysaccharide treatment in mice. Phytotherapy Research 2013;27:1270-6. https://doi.org/10.1002/ptr.4852.
  53. Vinoth Kumar R, Oh TW, Park YK. Anti-inflammatory effects of ginsenoside-Rh2 inhibits LPS-induced activation of microglia and overproduction of inflammatory mediators via modulation of TGF-β1/smad pathway. Neurochem Res 2016;41:951-7. https://doi.org/10.1007/s11064-015-1804-x.
  54. Ikram M, Jo MG, Park TJ, Kim MW, Khan I, Jo MH, et al. Oral administration of gintonin protects the brains of mice against aβ-induced alzheimer disease pathology: antioxidant and anti-inflammatory effects. Oxid Med Cell Longev 2021;2021:1-16. https://doi.org/10.1155/2021/6635552.
  55. Shin SJ, Nam Y, Park YH, Kim MJ, Lee E, Jeon SG, et al. Therapeutic effects of non-saponin fraction with rich polysaccharide from Korean red ginseng on aging and Alzheimer's disease. Free Radic Biol Med 2021;164:233-48. https://doi.org/10.1016/j.freeradbiomed.2020.12.454.
  56. Ghosal K, Stathopoulos A, Pimplikar SW. APP intracellular domain impairs adult neurogenesis in transgenic mice by inducing neuroinflammation. PLoS One 2010;5:e11866. https://doi.org/10.1371/journal.pone.0011866.
  57. Forloni G, Demicheli F, Giorgi S, Bendotti C, Angeretti N. Expression of amyloid precursor protein mRNAs in endothelial, neuronal and glial cells: modulation by interleukin-1. Mol Brain Res 1992;16:128-34. https://doi.org/10.1016/0169-328X(92)90202-M.
  58. Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflam 2008;5:37. https://doi.org/10.1186/1742-2094-5-37.
  59. Liu J, Yan X, Li L, Li Y, Zhou L, Zhang X, et al. Ginsenoside Rd improves learning and memory ability in APP transgenic mice. J Mol Neurosci 2015;57:522-8. https://doi.org/10.1007/s12031-015-0632-4.
  60. Zhang H, Su Y, Sun Z, Chen M, Han Y, Li Y, et al. Ginsenoside Rg1 alleviates Aβ deposition by inhibiting NADPH oxidase 2 activation in APP/PS1 mice. J Ginseng Res 2021;45:665-75. https://doi.org/10.1016/j.jgr.2021.03.003.
  61. Mandelkow E. Tau in Alzheimer's disease. Trends Cell Biol 1998;8:425-7. https://doi.org/10.1016/S0962-8924(98)01368-3.
  62. Metcalfe MJ, Figueiredo-Pereira ME. Relationship between tau pathology and neuroinflammation in Alzheimer's disease. Mount Sinai J Med: J Translat Personal Med 2010;77:50-8. https://doi.org/10.1002/msj.20163.
  63. Terada T, Yokokura M, Obi T, Bunai T, Yoshikawa E, Ando I, et al. In vivo direct relation of tau pathology with neuroinflammation in early Alzheimer's disease. J Neurol 2019;266:2186-96. https://doi.org/10.1007/s00415-019-09400-2.
  64. Houben S, de Fisenne MA, Ando K, vanden Dries V, Poncelet L, Yilmaz Z, et al. Intravenous injection of PHF-tau proteins from alzheimer brain exacerbates neuroinflammation, amyloid beta, and tau pathologies in 5XFAD transgenic mice. Front Mol Neurosci 2020;13. https://doi.org/10.3389/fnmol.2020.00106.
  65. Bellucci A, Westwood AJ, Ingram E, Casamenti F, Goedert M, Spillantini MG. Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am J Pathol 2004;165:1643-52. https://doi.org/10.1016/S0002-9440(10)63421-9.
  66. Sydow A, Hochgrafe K, Konen S, Cadinu D, Matenia D, Petrova O, et al. Age-dependent neuroinflammation and cognitive decline in a novel Ala152Thr-Tau transgenic mouse model of PSP and AD. Acta Neuropathol Commun 2016;4:17. https://doi.org/10.1186/s40478-016-0281-z.
  67. Shin SJ, Park YH, Jeon SG, Kim S, Nam Y, Oh SM, et al. Red ginseng inhibits tau aggregation and promotes tau dissociation in vitro. Oxid Med Cell Longev 2020;2020:1-12. https://doi.org/10.1155/2020/7829842.
  68. Zhang Y, Pi Z, Song F, Liu Z. Ginsenosides attenuate d-galactose- and AlCl3-inducedspatial memory impairment by restoring the dysfunction of the neurotransmitter systems in the rat model of Alzheimer's disease. J Ethnopharmacol 2016;194:188-95. https://doi.org/10.1016/j.jep.2016.09.007.
  69. Dong Y, Yu H, Li X, Bian K, Zheng Y, Dai M, et al. Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer's disease. J Neuroinflammation 2022;19:205. https://doi.org/10.1186/s12974-022-02567-y.
  70. Li L, Liu J, Yan X, Qin K, Shi M, Lin T, et al. Protective effects of ginsenoside Rd against okadaic acid-induced neurotoxicity in vivo and in vitro. J Ethnopharmacol 2011;138:135-41. https://doi.org/10.1016/j.jep.2011.08.068.
  71. Chen X, Huang T, Zhang J, Song J, Chen L, Zhu Y. Involvement of calpain and p25 of CDK5 pathway in ginsenoside Rb1's attenuation of β-amyloid peptide25-35-induced tau hyperphosphorylation in cortical neurons. Brain Res 2008;1200:99-106. https://doi.org/10.1016/j.brainres.2007.12.029.
  72. Weston LL, Jiang S, Chisholm D, Jantzie LL, Bhaskar K. Interleukin-10 deficiency exacerbates inflammation-induced tau pathology. J Neuroinflammation 2021;18:161. https://doi.org/10.1186/s12974-021-02211-1.
  73. Liu Y, Li J, Wang X, Liu Y, Zhang C, Chabalala H, et al. Ginsenoside Rb1 attenuates lipopolysaccharide-induced chronic neuroinflammation in mice by tuning glial cell polarization. J Tradit Chin Med Sci 2022;9:383-91. https://doi.org/10.1016/j.jtcms.2022.06.015.
  74. Chen C, Zhang H, Xu H, Zheng Y, Wu T, Lian Y. Ginsenoside Rb1 ameliorates cisplatin-induced learning and memory impairments. J Ginseng Res 2019;43:499-507. https://doi.org/10.1016/j.jgr.2017.07.009.
  75. Sveinbjornsdottir S. The clinical symptoms of Parkinson's disease. J Neurochem 2016;139:318-24. https://doi.org/10.1111/jnc.13691.
  76. Dauer W, Przedborski S. Parkinson's disease. Neuron 2003;39:889-909. https://doi.org/10.1016/S0896-6273(03)00568-3.
  77. Phani S, Loike JD, Przedborskia S. Neurodegeneration and inflammation in Parkinson's disease. Parkinsonism Relat Disord 2012;18. https://doi.org/10.1016/s1353-8020(11)70064-5.
  78. Koprich JB, Reske-Nielsen C, Mithal P, Isacson O. Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease. J Neuroinflammation 2008;5:8. https://doi.org/10.1186/1742-2094-5-8.
  79. Hunot S, Hirsch EC. Neuroinflammatory processes in Parkinson's disease. Ann Neurol 2003;53. https://doi.org/10.1002/ana.10481.
  80. Choi JH, Jang M, Nah SY, Oh S, Cho IH. Multitarget effects of Korean Red Ginseng in animal model of Parkinson's disease: antiapoptosis, antioxidant, antiinflammation, and maintenance of blood-brain barrier integrity. J Ginseng Res 2018;42:379-88. https://doi.org/10.1016/j.jgr.2018.01.002.
  81. Choi JH, Jang M, Oh S, Nah SY, Cho IH. Multi-Target protective effects of gintonin in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Mediated model of Parkinson's disease via lysophosphatidic acid receptors. Front Pharmacol 2018;9. https://doi.org/10.3389/fphar.2018.00515.
  82. Zaafan MA, Abdelhamid AM, Ibrahim SM. The protective effect of Korean red ginseng against rotenone-induced Parkinson's disease in rat model: modulation of nuclear factor-κβ and caspase-3. Curr Pharm Biotechnol 2019;20:588-94. https://doi.org/10.2174/1389201020666190611122747.
  83. 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. https://doi.org/10.4103/1673-5374.257536.
  84. Sun XC, Ren XF, Chen L, Gao XQ, Xie JX, Chen WF. 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 2016;155:94-103. https://doi.org/10.1016/j.jsbmb.2015.09.040.
  85. Zhang X, Wang Y, Ma C, Yan Y, Yang Y, Wang X, et al. Ginsenoside Rd and ginsenoside Re offer neuroprotection in a novel model of Parkinson's disease. Am J Neurodegener Dis 2016;5:52-61.
  86. Lin W-M, Zhang Y-M, Moldzio R, Rausch W-D. Ginsenoside Rd attenuates neuroinflammation of dopaminergic cells in culture. Neuropsychiat Disord Integrat Approach, Vienna: Springer Vienna; n.d., p. 105-112. https://doi.org/10.1007/978-3-211-73574-9_13.
  87. Zhou T, Zu G, Wang X, Zhang X, Li S, Liang Z, et al. Immunomodulatory and neuroprotective effects of ginsenoside Rg1 in the MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) -induced mouse model of Parkinson's disease. Int Immunopharmacol 2015;29:334-43. https://doi.org/10.1016/j.intimp.2015.10.032.
  88. Jeon H, Bae CH, Lee Y, Kim HY, Kim S. Korean red ginseng suppresses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced inflammation in the substantia nigra and colon. Brain Behav Immun 2021;94:410-23. https://doi.org/10.1016/j.bbi.2021.02.028.
  89. Stefanis L. α-Synuclein in Parkinson's disease. Cold Spring Harb Perspect Med 2012;2. https://doi.org/10.1101/cshperspect.a009399.
  90. Recchia A, Debetto P, Negro A, Guidolin D, Skaper SD, Giusti P. α-Synuclein and Parkinson's disease. The FASEB Journal 2004;18:617-26. https://doi.org/10.1096/fj.03-0338rev.
  91. Jo MG, Ikram M, Jo MH, Yoo L, Chung KC, Nah SY, et al. Gintonin mitigates MPTP-induced loss of nigrostriatal dopaminergic neurons and accumulation of α-synuclein via the Nrf2/HO-1 pathway. Mol Neurobiol 2019;56:39-55. https://doi.org/10.1007/s12035-018-1020-1.
  92. Ardah MT, Paleologou KE, Lv G, Menon SA, Abul Khair SB, Lu JH, et al. Ginsenoside Rb1 inhibits fibrillation and toxicity of alpha-synuclein and disaggregates preformed fibrils. Neurobiol Dis 2015;74:89-101. https://doi.org/10.1016/j.nbd.2014.11.007.
  93. Roos RA. Huntington's disease: a clinical review. Orphanet J Rare Dis 2010;5:40. https://doi.org/10.1186/1750-1172-5-40.
  94. Hsiao HY, Chen YC, Chen HM, Tu PH, Chern Y. A critical role of astrocyte-mediated nuclear factor-κB-dependent inflammation in Huntington's disease. Hum Mol Genet 2013;22:1826-42. https://doi.org/10.1093/hmg/ddt036.
  95. Yang X, Chu S, Wang Z, Li F, Yuan Y, Chen N. Ginsenoside Rg1 exerts neuroprotective effects in 3-nitropronpionic acid-induced mouse model of Huntington's disease via suppressing MAPKs and NF-κB pathways in the striatum. Acta Pharmacol Sin 2021;42:1409-21. https://doi.org/10.1038/s41401-020-00558-4.
  96. Jang M, Choi JH, Chang Y, Lee SJ, Nah SY, Cho IH. Gintonin, a ginseng-derived ingredient, as a novel therapeutic strategy for Huntington's disease: activation of the Nrf2 pathway through lysophosphatidic acid receptors. Brain Behav Immun 2019;80:146-62. https://doi.org/10.1016/j.bbi.2019.03.001.
  97. Lee M, Ban JJ, Won BH, Im W, Kim M. Therapeutic potential of ginsenoside Rg3 and Rf for Huntington's disease. In Vitro Cell Dev Biol Anim 2021;57:641-8. https://doi.org/10.1007/s11626-021-00595-1.
  98. Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers 2017;3:17071. https://doi.org/10.1038/nrdp.2017.71.
  99. Brites D, Vaz AR. Microglia centered pathogenesis in ALS: insights in cell interconnectivity. Front Cell Neurosci 2014;8. https://doi.org/10.3389/fncel.2014.00117.
  100. Jiang F, DeSilva S, Turnbull J. Beneficial effect of ginseng root in SOD-1 (G93A) transgenic mice. J Neurol Sci 2000;180:52-4. https://doi.org/10.1016/S0022-510X(00)00421-4.
  101. Cai M, Yang EJ. Ginsenoside Re attenuates neuroinflammation in a symptomatic ALS animal model. Am J Chinese Med 2016;44:401-13. https://doi.org/10.1142/S0192415X16500233.
  102. Nam M, Choi JH, Choi SH, Cho HJ, Cho YJ, Rhim H, et al. Ginseng gintonin alleviates neurological symptoms in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis through lysophosphatidic acid 1 receptor. J Ginseng Res 2021;45:390-400. https://doi.org/10.1016/j.jgr.2020.04.002.
  103. Chen W, Yao P, Vong CT, Li X, Chen Z, Xiao J, et al. Ginseng: a bibliometric analysis of 40-year journey of global clinical trials. J Adv Res 2021;34:187-97. https://doi.org/10.1016/j.jare.2020.07.016.