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.

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

Abstract

Huntington’s disease (HD) is one of main neurodegenerative diseases, characterized by striatal atrophy, involuntary movements, and motor incoordination. Ginsenoside Rg1 (Rg1), an active ingredient in ginseng, possesses a variety of neuroprotective effects with low toxicity and side effects. In this study, we investigated the potential therapeutic effects of Rg1 in a mouse model of HD and explored the underlying mechanisms. HD was induced in mice by injection of 3-nitropropionic acid (3-NP, i.p.) for 4 days. From the first day of 3-NP injection, the mice were administered Rg1 (10, 20, 40 mg·kg−1, p.o.) for 5 days. We showed that oral pretreatment with Rg1 alleviated 3-NP-induced body weight loss and behavioral defects. Furthermore, pretreatment with Rg1 ameliorated 3-NP-induced neuronal loss and ultrastructural morphological damage in the striatum. Moreover, pretreatment with Rg1 reduced 3-NP-induced apoptosis and inhibited the activation of microglia, inflammatory mediators in the striatum. We revealed that Rg1 exerted neuroprotective effects by suppressing 3-NP-induced activation of the MAPKs and NF-κΒ signaling pathways in the striatum. Thus, our results suggest that Rg1 exerts therapeutic effects on 3-NP-induced HD mouse model via suppressing MAPKs and NF-κΒ signaling pathways. Rg1 may be served as a novel therapeutic option for HD.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Scheme of the experimental procedure.
Fig. 2: Rg1 alleviated body weight loss and behavioral defects induced by 3-NP.
Fig. 3: Rg1 ameliorated striatal neuronal loss induced by 3-NP.
Fig. 4: Rg1 alleviated the striatal ultrastructural morphological damage induced by 3-NP.
Fig. 5: Rg1 reduced the striatal apoptosis induced by 3-NP.
Fig. 6: Rg1 inhibited the striatal microglial activation induced by 3-NP.
Fig. 7: Rg1 decreased the productions of proinflammatory cytokines induced by 3-NP.
Fig. 8: Rg1 suppressed activations of the MAPKs and NF-κB pathways induced by 3-NP.
Fig. 9: The schematic diagram for possible mechanisms of Rg1’s neuroprotective effects in 3-NP induced HD mouse model.

References

  1. 1.

    Walter C, Clemens LE, Muller AJ, Fallier-Becker P, Proikas-Cezanne T, Riess O, et al. Activation of AMPK-induced autophagy ameliorates Huntington disease pathology in vitro. Neuropharmacology. 2016;108:24–38.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev. 2010;90:905–81.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Snowden JS. The neuropsychology of Huntington’s disease. Arch Clin Neuropsychol. 2017;32:876–87.

    PubMed  Article  Google Scholar 

  4. 4.

    Dargaei Z, Bang JY, Mahadevan V, Khademullah CS, Bedard S, Parfitt GM, et al. Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model. Proc Natl Acad Sci USA. 2018;115:E1618–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Sepers MD, Smith-Dijak A, LeDue J, Kolodziejczyk K, Mackie K, Raymond LA. Endocannabinoid-specific impairment in synaptic plasticity in striatum of Huntington’s disease mouse model. J Neurosci. 2018;38:544–54.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, et al. Huntington disease. Nat Rev Dis Prim. 2015;1:15005.

    PubMed  Article  Google Scholar 

  7. 7.

    Jang M, Cho IH. Sulforaphane ameliorates 3-nitropropionic acid-induced striatal toxicity by activating the Keap1-Nrf2-ARE pathway and inhibiting the MAPKs and NF-κB pathways. Mol Neurobiol. 2015;53:2619–35.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Brouillet E. The 3‐NP model of striatal neurodegeneration. Curr Protoc Neurosci. 2014;67:9.48.

    Article  Google Scholar 

  9. 9.

    Jamwal S, Kumar P. Spermidine ameliorates 3-nitropropionic acid (3-NP)-induced striatal toxicity: Possible role of oxidative stress, neuroinflammation, and neurotransmitters. Physiol Behav. 2016;155:180–7.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Wang L, Wang J, Yang L, Zhou SM, Guan SY, Yang LK, et al. Effect of Praeruptorin C on 3-nitropropionic acid induced Huntington's disease-like symptoms in mice. Biomed Pharmacother. 2017;86:81–7.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Dhadde SB, Nagakannan P, Roopesh M, Anand Kumar SR, Thippeswamy BS, Veerapur VP, et al. Effect of embelin against 3-nitropropionic acid-induced Huntington’s disease in rats. Biomed Pharmacother. 2016;77:52–8.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Jang M, Lee MJ, Cho IH. Ethyl pyruvate ameliorates 3-nitropropionic acid-induced striatal toxicity through anti-neuronal cell death and anti-inflammatory mechanisms. Brain Behav Immun. 2014;38:151–65.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Lai JL, Liu YH, Liu C, Qi MP, Liu RN, Zhu XF, et al. Indirubin inhibits LPS-induced inflammation via TLR4 abrogation mediated by the NF-κB and MAPK signaling pathways. Inflammation 2017;40:1–12.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Haddad JJ. N-methyl-D-aspartate (NMDA) and the regulation of mitogen-activated protein kinase (MAPK) signaling pathways: a revolving neurochemical axis for therapeutic intervention? Prog Neurobiol. 2005;77:252–82.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Jiao D, Jiang Q, Liu Y, Ji L. Nephroprotective effect of wogonin against cadmium-induced nephrotoxicity via inhibition of oxidative stress-induced MAPK and NF-kB pathway in Sprague Dawley rats. Hum Exp Toxicol. 2019;38:1082–91.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Santana-Martinez RA, Leon-Contreras JC, Barrera-Oviedo D, Pedraza-Chaverri J, Hernandez-Pando R, Maldonado PD. Sustained activation of JNK induced by quinolinic acid alters the BDNF/TrkB axis in the rat striatum. Neuroscience 2018;383:22–32.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Subramaniam S, Unsicker K. ERK and cell death: ERK1/2 in neuronal death. FEBS J. 2010;277:22–9.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Bodai L, Marsh JL. A novel target for Huntington’s disease: ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington’s disease and its upregulation ameliorates pathology. Bioessays. 2012;34:142–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Fusco FR, Anzilotti S, Giampa C, Dato C, Laurenti D, Leuti A, et al. Changes in the expression of extracellular regulated kinase (ERK1/2) in the R6/2 mouse model of Huntington’s disease after phosphodiesterase IV inhibition. Neurobiol Dis. 2012;46:225–33.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Yusuf IO, Cheng PH, Chen HM, Chang YF, Chang CY, Yang HI, et al. Fibroblast growth factor 9 suppresses striatal cell death dominantly through ERK signaling in Huntington’s disease. Cell Physiol Biochem. 2018;48:605–17.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Napolitano M, Zei D, Centonze D, Palermo R, Bernardi G, Vacca A, et al. NF-κB/NOS cross-talk induced by mitochondrial complex II inhibition: implications for Huntington’s disease. Neurosci Lett. 2008;434:241–6.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Wang KS, Li J, Wang Z, Mi C, Ma J, Piao LX, et al. Artemisinin inhibits inflammatory response via regulating NF-kappaB and MAPK signaling pathways. Immunopharmacol Immunotoxicol. 2017;39:28–36.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Kim KH, Lee D, Lee HL, Kim C-E, Jung K, Kang KS. Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative diseases: past findings and future directions. J Ginseng Res. 2018;42:239–47.

    PubMed  Article  Google Scholar 

  24. 24.

    Zhou T, Zu G, Zhang X, Wang X, Li S, Gong X, et al. Neuroprotective effects of ginsenoside Rg1 through the Wnt/β-catenin signaling pathway in both in vivo and in vitro models of Parkinson’s disease. Neuropharmacology. 2016;101:480–9.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    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 alpha-synuclein abnormalities in the substantia nigra. Toxicol Lett. 2016;243:7–21.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Jiang W, Wang Z, Jiang Y, Lu M, Li X. Ginsenoside Rg1 ameliorates motor function in an animal model of Parkinson’s disease. Pharmacology. 2015;96:25–31.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Xu L, Chen WF, Wong MS. Ginsenoside Rg1 protects dopaminergic neurons in a rat model of Parkinson’s disease through the IGF-I receptor signalling pathway. Br J Pharmacol. 2009;158:738–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Liu Q, Kou JP, Yu BY. Ginsenoside Rg1 protects against hydrogen peroxide-induced cell death in PC12 cells via inhibiting NF-kappaB activation. Neurochem Int. 2011;58:119–25.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Zhu J, Mu X, Zeng J, Xu C, Liu J, Zhang M, et al. Ginsenoside Rg1 prevents cognitive impairment and hippocampus senescence in a rat model of D-galactose-induced aging. PLoS One. 2014;9:e101291.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31.

    Jang M, Lee MJ, Kim CS, Cho IH. Korean red ginseng extract attenuates 3-nitropropionic acid-induced Huntington’s-like symptoms. Evid Based Complement Altern Med. 2013;2013:237207.

    Google Scholar 

  32. 32.

    Gao Y, Chu SF, Li JP, Zhang Z, Yan JQ, Wen ZL, et al. Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease. Acta Pharmacol Sin. 2015;36:311–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Jamwal S, Kumar P. L-theanine, a component of green tea prevents 3-nitropropionic acid (3-NP)-induced striatal toxicity by modulating nitric oxide pathway. Mol Neurobiol. 2016;54:2327–37.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Navarrete F, Garcia-Gutierrez MS, Laborda J, Manzanares J. Deletion of Dlk2 increases the vulnerability to anxiety-like behaviors and impairs the anxiolytic action of alprazolam. Psychoneuroendocrinology. 2017;85:134–41.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Zhang Y, Jiang YY, Shao S, Zhang C, Liu FY, Wan Y, et al. Inhibiting medial septal cholinergic neurons with DREADD alleviated anxiety-like behaviors in mice. Neurosci Lett. 2017;638:139–44.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Wen L, Zhang QS, Heng Y, Chen Y, Wang S, Yuan YH, et al. NLRP3 inflammasome activation in the thymus of MPTP-induced Parkinsonian mouse model. Toxicol Lett. 2018;288:1–8.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Kroymann J, Mitchell-Olds T. Epistasis and balanced polymorphism influencing complex trait variation. Nature. 2005;435:95–8.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Feng S, Xing C, Shen T, Qiao Y, Wang R, Chen J, et al. Abnormal paraventricular nucleus of hypothalamus and growth retardation associated with loss of nuclear receptor Gene COUP-TFII. Sci Rep. 2017;7:5282.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Song XY, Hu JF, Chu SF, Zhang Z, Xu S, Yuan YH, et al. Ginsenoside Rg1 attenuates okadaic acid induced spatial memory impairment by the GSK3β/tau signaling pathway and the Aβ formation prevention in rats. Eur J Pharmacol. 2013;710:29–38.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Chen C, Chu SF, Ai QD, Zhang Z, Guan FF, Wang SS, et al. CKLF1 aggravates focal cerebral ischemia injury at early stage partly by modulating microglia/macrophage toward M1 polarization through CCR4. Cell Mol Neurobiol. 2019;39:651–69.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Sun H, Tang Y, Guan X, Li L, Wang D. Effects of selective hypothermia on blood-brain barrier integrity and tight junction protein expression levels after intracerebral hemorrhage in rats. Biol Chem. 2013;394:1317–24.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Zuo Y, Huang L, Enkhjargal B, Xu W, Umut O, Travis ZD, et al. Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPARγ/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in rats. J Neuroinflammation. 2019;16:47.

    PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Sebastianutto I, Cenci MA, Fieblinger T. Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington’s disease. Neurobiol Dis. 2017;105:117–31.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Cho KJ, Cheon SY, Kim GW. Apoptosis signal-regulating kinase 1 mediates striatal degeneration via the regulation of C1q. Sci Rep. 2016;6:18840.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Armulik A, Genové G, Mäe M, Nisancioglu MH, Wallgard E, Niaudet C, et al. Pericytes regulate the blood–brain barrier. Nature. 2010;468:557–61.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Andre R, Carty L, Tabrizi SJ. Disruption of immune cell function by mutant huntingtin in Huntington’s disease pathogenesis. Curr Opin Pharmacol. 2016;26:33–8.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Kim YK, Na KS, Myint AM, Leonard BE. The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:277–84.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull. 2012;87:10–20.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Hanna DM, Tadros MG, Khalifa AE. ADIOL protects against 3-NP-induced neurotoxicity in rats: Possible impact of its anti-oxidant, anti-inflammatory and anti-apoptotic actions. Prog Neuropsychopharmacol Biol Psychiatry. 2015;60:36–51.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Jimenez-Sanchez M, Licitra F, Underwood BR, Rubinsztein DC. Huntington’s disease: Mechanisms of pathogenesis and therapeutic strategies. Cold Spring Harb Perspect Med. 2017;7:a024240.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. 51.

    Silva-Palacios A, Ostolga-Chavarría M, Buelna-Chontal M, Garibay C, Hernández-Reséndiz S, Roldán FJ, et al. 3-NP-induced Huntington’s-like disease impairs Nrf2 activation without loss of cardiac function in aged rats. Exp Gerontol. 2017;96:89–98.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Elbaz EM, Helmy HS, El-Sahar AE, Saad MA, Sayed RH. Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3-NP-induced Huntington’s disease model rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/beta-catenin signalling pathways. Neurochem Int. 2019;131:104548.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Torres‐Cruz FM, Mendoza E, Vivar‐Cortés IC, García‐Sierra F, Hernández‐Echeagaray E. Do BDNF and NT‐4/5 exert synergistic or occlusive effects on corticostriatal transmission in a male mouse model of Huntington’s disease? J Neurosci Res. 2019;97:1665–77.

    PubMed  Google Scholar 

  54. 54.

    Sgambato-Faure V, Qian Y, Forssberg H, Diaz Heijtz R. Motor skill learning is associated with phase-dependent modifications in the striatal cAMP/PKA/DARPP-32 signaling pathway in rodents. PLoS One. 2015;10:e0140974.

    Article  CAS  Google Scholar 

  55. 55.

    Xenias HS, Ibanez-Sandoval O, Koos T, Tepper JM. Are striatal tyrosine hydroxylase interneurons dopaminergic? J Neurosci. 2015;35:6584–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Domenici MR, Chiodi V, Averna M, Armida M, Pezzola A, Pepponi R, et al. Neuronal adenosine A2A receptor overexpression is neuroprotective towards 3-nitropropionic acid-induced striatal toxicity: a rat model of Huntington’s disease. Purinergic Signal. 2018;14:235–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Ramachandran S, Thangarajan S. Thymoquinone loaded solid lipid nanoparticles counteracts 3-nitropropionic acid induced motor impairments and neuroinflammation in rat model of Huntington’s disease. Metab Brain Dis. 2018;33:1459–70.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology. 2010;129:154–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Xu L, He D, Bai Y. Microglia-mediated inflammation and neurodegenerative disease. Mol Neurobiol. 2015;53:6709–15.

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Thome AD, Harms AS, Volpicelli-Daley LA, Standaert DG. microRNA-155 Regulates alpha-synuclein-induced inflammatory responses in models of Parkinson disease. J Neurosci. 2016;36:2383–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N. Y.). 2018;4:575–90.

    Article  Google Scholar 

  62. 62.

    Pido-Lopez J, Andre R, Benjamin AC, Ali N, Farag S, Tabrizi SJ, et al. In vivo neutralization of the protagonist role of macrophages during the chronic inflammatory stage of Huntington’s disease. Sci Rep. 2018;8:11447.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Siew JJ, Chen HM, Chen HY, Chen HL, Chen CM, Soong BW, et al. Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease. Nat Commun. 2019;10:3473.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    Liu CY, Wang X, Liu C, Zhang HL. Pharmacological targeting of microglial activation: New therapeutic approach. Front Cell Neurosci. 2019;13:514.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Paldino E, Balducci C, La Vitola P, Artioli L, D’Angelo V, Giampà C, et al. Neuroprotective effects of doxycycline in the R6/2 mouse model of Huntington’s disease. Mol Neurobiol. 2020;57:1889–903.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Chang KH, Wu YR, Chen YC, Chen CM. Plasma inflammatory biomarkers for Huntington’s disease patients and mouse model. Brain Behav Immun. 2015;44:121–7.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Kalonia H, Kumar A. Suppressing inflammatory cascade by cyclo-oxygenase inhibitors attenuates quinolinic acid induced Huntington’s disease-like alterations in rats. Life Sci. 2011;88:784–91.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Valadao PAC, Oliveira BDS, Joviano-Santos JV, Vieira ELM, Rocha NP, Teixeira AL, et al. Inflammatory changes in peripheral organs in the BACHD murine model of Huntington’s disease. Life Sci. 2019;232:116653.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Sweeney MD, Sagare AP, Zlokovic BV. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Duran-Vilaregut J, del Valle J, Manich G, Camins A, Pallàs M, Vilaplana J, et al. Role of matrix metalloproteinase-9 (MMP-9) in striatal blood-brain barrier disruption in a 3-nitropropionic acid model of Huntington’s disease. Neuropathol Appl Neurobiol. 2011;37:525–37.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Lin CY, Hsu YH, Lin MH, Yang TH, Chen HM, Chen YC, et al. Neurovascular abnormalities in humans and mice with Huntington’s disease. Exp Neurol. 2013;250:20–30.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Gao XQ, Du ZR, Yuan LJ, Zhang WD, Chen L, Teng JJ, et al. Ginsenoside Rg1 exerts anti-inflammatory effects via G protein-coupled estrogen receptor in lipopolysaccharide-induced microglia activation. Front Neurosci. 2019;13:1168.

    PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    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.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Li Y, Guan Y, Wang Y, Yu CL, Zhai FG, Guan LX. Neuroprotective effect of the ginsenoside Rg1 on cerebral ischemic injury in vivo and in vitro is mediated by PPARγ-regulated antioxidative and anti-inflammatory pathways. Evid Based Complement Altern Med. 2017;2017:7842082.

    Google Scholar 

  75. 75.

    Hu JF, Song XY, Chu SF, Chen J, Ji HJ, Chen XY, et al. Inhibitory effect of ginsenoside Rg1 on lipopolysaccharide-induced microglial activation in mice. Brain Res. 2011;1374:8–14.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Laprairie RB, Warford JR, Hutchings S, Robertson GS, Kelly MEM, Denovan-Wright EM. The cytokine and endocannabinoid systems are co-regulated by NF-κB p65/RelA in cell culture and transgenic mouse models of Huntington’s disease and in striatal tissue from Huntington’s disease patients. J Neuroimmunol. 2014;267:61–72.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Mahdy HM, Mohamed MR, Emam MA, Karim AM, Abdel-Naim AB, Khalifa AE. The anti-apoptotic and anti-inflammatory properties of puerarin attenuate 3-nitropropionic-acid induced neurotoxicity in rats. Can J Physiol Pharm. 2014;92:252–8.

    CAS  Article  Google Scholar 

  78. 78.

    Liu SY, Yu XL, Zhu J, Liu XM, Zhang Y, Dong QX, et al. Intravenous immunoglobulin ameliorates motor and cognitive deficits and neuropathology in R6/2 mouse model of Huntington’s disease by decreasing mutant huntingtin protein level and normalizing NF-kappaB signaling pathway. Brain Res. 2018;1697:21–33.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Kulasekaran G, Ganapasam S. Neuroprotective efficacy of naringin on 3-nitropropionic acid-induced mitochondrial dysfunction through the modulation of Nrf2 signaling pathway in PC12 cells. Mol Cell Biochem. 2015;409:199–211.

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Fang F, Chen X, Huang T, Lue LF, Luddy JS, Yan SS. Multi-faced neuroprotective effects of ginsenoside Rg1 in an Alzheimer mouse model. Biochim Biophys Acta. 2012;1822:286–92.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Chen XC, Zhou YC, Chen Y, Zhu YG, Fang F, Chen LM. Ginsenoside Rg1 reduces MPTP-induced substantia nigra neuron loss by suppressing oxidative stress. Acta Pharmacol Sin. 2005;26:56–62.

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Chu SF, Zhang Z, Zhou X, He WB, Chen C, Luo P, et al. Ginsenoside Rg1 protects against ischemic/reperfusion-induced neuronal injury through miR-144/Nrf2/ARE pathway. Acta Pharmacol Sin. 2019;40:13–25.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Shi Q, He Q, Chen W, Long J, Zhang B. Ginsenoside Rg1 abolish imiquimod‐induced psoriasis‐like dermatitis in BALB/c mice via downregulating NF‐κB signaling pathway. J Food Biochem. 2019;43:e13032.

    PubMed  Google Scholar 

  85. 85.

    Mo J, Zhou Y, Yang R, Zhang P, He B, Yang J, et al. Ginsenoside Rg1 ameliorates palmitic acid-induced insulin resistance in HepG2 cells in association with modulating Akt and JNK activity. Pharmacol Rep. 2019;71:1160–7.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Luo M, Yan D, Sun Q, Tao J, Xu L, Sun H, et al. Ginsenoside Rg1 attenuates cardiomyocyte apoptosis and inflammation via the TLR4/NF‐kB/NLRP3 pathway. J Cell Biochem. 2020;121:2994–3004.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Zheng T, Jiang H, Jin R, Zhao Y, Bai Y, Xu H, et al. Ginsenoside Rg1 attenuates protein aggregation and inflammatory response following cerebral ischemia and reperfusion injury. Eur J Pharmacol. 2019;853:65–73.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Li W, Chu Y, Zhang L, Yin L, Li L. Ginsenoside Rg1 attenuates tau phosphorylation in SK-N-SH induced by Aβ‐stimulated THP-1 supernatant and the involvement of p38 pathway activation. Life Sci. 2012;91:809–15.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Shi C, Zheng DD, Fang L, Wu F, Kwong WH, Xu J. Ginsenoside Rg1 promotes nonamyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK and PI3K/Akt. Biochim Biophys Acta. 2012;1820:453–60.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Ge KL, Chen WF, Xie JX, Wong MS. Ginsenoside Rg1 protects against 6-OHDA-induced toxicity in MES23.5 cells via Akt and ERK signaling pathways. J Ethnopharmacol. 2010;127:118–23.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Ye Y, Shan Y, Bao C, Hu Y, Wang L. Ginsenoside Rg1 protects against hind-limb ischemia reperfusion induced lung injury via NF-κB/COX-2 signaling pathway. Int Immunopharmacol. 2018;60:96–103.

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Zhang XJ, He C, Li P, Su H, Wan JB. Ginsenoside Rg1, a potential JNK inhibitor, protects against ischemia/reperfusion-induced liver damage. J Funct Foods. 2015;15:580–92.

    CAS  Article  Google Scholar 

  93. 93.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Liu P, Li Y, Liu D, Ji X, Chi T, Li L, et al. Tolfenamic acid attenuates 3-nitropropionic acid-induced biochemical alteration in mice. Neurochem Res. 2018;43:1938–46.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain barrier: From physiology to disease and back. Physiol Rev. 2019;99:21–78.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81773924, 81873026, and 81973499), the CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-004), the Drug Innovation Major Project (2018ZX09711001-003-005 and 2018ZX09711001-009-013), and the Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (BZ0150).

Author information

Affiliations

Authors

Contributions

XY, SFC, and NHC designed the study; XY, ZZW, and FFL performed the experiments; ZZW, FFL, and YHY contributed analytic tools; XY and SFC analyzed the results; and XY wrote the manuscript.

Corresponding author

Correspondence to Nai-hong Chen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yang, X., Chu, Sf., Wang, Zz. et al. 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 42, 1409–1421 (2021). https://doi.org/10.1038/s41401-020-00558-4

Download citation

Keywords

  • Huntington’s disease
  • ginsenoside Rg1
  • 3-nitropropionic acid
  • striatum
  • neuroprotective effects
  • MAPKs
  • NF-κB

Further reading

Search

Quick links