DOI QR코드

DOI QR Code

Korean Red Ginseng and Rb1 facilitate remyelination after cuprizone diet-induced demyelination

  • Oh Wook, Kwon (Department of Integrative Biosciences, University of Brain Education) ;
  • Dalnim, Kim (Korea Institute of Brain Science) ;
  • Eugene, Koh (Temasek Life Sciences Laboratories) ;
  • Hyun-Jeong, Yang (Department of Integrative Biosciences, University of Brain Education)
  • 투고 : 2022.04.10
  • 심사 : 2022.09.27
  • 발행 : 2023.03.02

초록

Background: Demyelination has been observed in neurological disorders, motivating researchers to search for components for enhancing remyelination. Previously we found that Rb1, a major ginsenoside in Korean Red Ginseng (KRG), enhances myelin formation. However, it has not been studied whether Rb1 or KRG function in remyelination after demyelination in vivo. Methods: Mice were fed 0.2% cuprizone-containing chow for 5 weeks and returned to normal chow with daily oral injection of vehicle, KRG, or Rb1 for 3 weeks. Brain sections were stained with luxol fast blue (LFB) staining or immunohistochemistry. Primary oligodendrocyte or astrocyte cultures were subject to normal or stress condition with KRG or Rb1 treatment to measure gene expressions of myelin, endoplasmic reticulum (ER) stress, antioxidants and leukemia inhibitory factor (LIF). Results: Compared to the vehicle, KRG or Rb1 increased myelin levels at week 6.5 but not 8, when measured by the LFB+ or GST-pi+ area within the corpus callosum. The levels of oligodendrocyte precursor cells, astrocytes, and microglia were high at week 5, and reduced afterwards but not changed by KRG or Rb1. In primary oligodendrocyte cultures, KRG or Rb1 increased expression of myelin genes, ER stress markers, and antioxidants. Interestingly, under cuprizone treatment, elevated ER stress markers were counteracted by KRG or Rb1. Under rotenone treatment, reduced myelin gene expressions were recovered by Rb1. In primary astrocyte cultures, KRG or Rb1 decreased LIF expression. Conclusion: KRG and Rb1 may improve myelin regeneration during the remyelination phase in vivo, potentially by directly promoting myelin gene expression.

키워드

과제정보

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1I1A3A04038150) and a grant (2020-2021) from the Korean Society of Ginseng.

참고문헌

  1. Salzer JL, Zalc B, Myelination. Curr Biol 2016;26:R971-5.  https://doi.org/10.1016/j.cub.2016.07.074
  2. Xin W, Chan JR. Myelin plasticity: sculpting circuits in learning and memory. Nat Rev Neurosci 2020;21:682-94.  https://doi.org/10.1038/s41583-020-00379-8
  3. Hill RA, Li AM, Grutzendler J. Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain. Nat Neurosci 2018;21:683-95.  https://doi.org/10.1038/s41593-018-0120-6
  4. Dvorak AV, Swift-LaPointe T, Vavasour IM, LE Lee, Abel S, Russell-Schulz B, Graf C, Wurl A, Liu H, Laule C, et al. An atlas for human brain myelin content throughout the adult life span. Sci. Rep. 2021;11:269. 
  5. Bouhrara M, Reiter DA, Bergeron CM, Zukley LM, Ferrucci L, Resnick SM, Spencer G. Evidence of demyelination in mild cognitive impairment and dementia using a direct and specific magnetic resonance imaging measure of myelin content. Alzheimers Dement 2018;14:998-1004.  https://doi.org/10.1016/j.jalz.2018.03.007
  6. Rahmanzadeh R, Lu PJ, Barakovic M, Weigel M, Maggi P, Nguyen TD, Schiavi S, Daducci A, Rosa FL, Schaedelin S, et al. Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging. Brain 2021;144:1684-96.  https://doi.org/10.1093/brain/awab088
  7. Hyun SH, Bhilare KD, , G In, Park CK, Kim JH. Effects of panax ginseng and ginsenosides on oxidative stress and cardiovascular diseases: pharmacological and therapeutic roles. J Ginseng Res 2022;46:33-8.  https://doi.org/10.1016/j.jgr.2021.07.007
  8. Lee YY, Kim SD, Park SC, Rhee MH. Panax ginseng: inflammation, platelet aggregation, thrombus formation, and atherosclerosis crosstalk. J Ginseng Res 2022;46:54-61.  https://doi.org/10.1016/j.jgr.2021.09.003
  9. Smith I, Williamson EM, Putnam S, Farrimond J, Whalley BJ. Effects and mechanisms of ginseng and ginsenosides on cognition. Nutr Rev 2014;72:319-33.  https://doi.org/10.1111/nure.12099
  10. Dong L, Wang Y, Lv J, Zhang H, Jiang N, Lu C, Xu P, Liu X. Memory enhancement of fresh ginseng on deficits induced by chronic restraint stress in mice. Nutr. Neurosci. 2019;22:235-42.  https://doi.org/10.1080/1028415x.2017.1373928
  11. Kim HJ, Jung SW, Kim SY, Cho IH, Kim HC, Rhim H, Kim M, Nah S. Panax ginseng as an adjuvant treatment for alzheimer's disease. J. Ginseng. Res. 2018;42:401-11.  https://doi.org/10.1016/j.jgr.2017.12.008
  12. Nasrabady SE, Rizvi B, Goldman JE, Brickman AM. White matter changes in alzheimer's disease: a focus on myelin and oligodendrocytes. Acta Neuropathol Commun 2018;6:22. 
  13. Lubetzki C, Zalc B, Williams A, Stadelmann C, Stankoff B. Remyelination in multiple sclerosis: from basic science to clinical translation. Lancet Neurol 2020;19:678-88.  https://doi.org/10.1016/s1474-4422(20)30140-x
  14. Shin BK, Kwon SW, Park JH. Chemical diversity of ginseng saponins from panax ginseng. J Ginseng Res 2015;39:287-98.  https://doi.org/10.1016/j.jgr.2014.12.005
  15. Han B, Park M, Han Y. Chemical and biochemical studies on non-saponin constituents of Korean ginseng. Journal of Ginseng Research 1992;16:228-34. 
  16. Pyo M, Choi S, Hwang S, Shin T, Lee B, Lee S, Lim Y, Kim D, Nah S. Novel glycolipoproteins from ginseng. J. Ginseng. Res. 2011;35:92-103.  https://doi.org/10.5142/jgr.2011.35.1.092
  17. Lee A, Kwon OW, Jung KR, Song GJ, Yang HJ. The effects of Korean red ginsengderived components on oligodendrocyte lineage cells: distinct facilitatory roles of the non-saponin and saponin fractions, and rb1, in proliferation, differentiation and myelination. J Ginseng Res 2022;46:104-14.  https://doi.org/10.1016/j.jgr.2021.04.007
  18. Mijan MA, Kim JY, Moon SY, Choi SH, Nah SY, Yang HJ. Gintonin enhances proliferation, late stage differentiation, and cell survival from endoplasmic reticulum stress of oligodendrocyte lineage cells. Front Pharmacol 2019;10:1211. 
  19. Ahmed T, Raza SH, Maryam A, Setzer WN, Braidy N, Nabavi SF, Oliveira MR, Nabavi SM. Ginsenoside rb1 as a neuroprotective agent: a review. Brain Res. Bull. 2016;125:30-43.  https://doi.org/10.1016/j.brainresbull.2016.04.002
  20. Zhou P, Xie W, He S, Sun Y, Meng X, Sun G, Sun X. Ginsenoside rb1 as an antidiabetic agent and its underlying mechanism analysis. Cells 2019;8. 
  21. Zhou P, Xie W, Sun Y, Dai Z, Li G, Sun G, Sun X. Ginsenoside rb1 and mitochondria: a short review of the literature. Mol. Cell Probes 2019;43:1-5.  https://doi.org/10.1016/j.mcp.2018.12.001
  22. Chen Y, Li YY, Wang S, Zhou T, Chen NH, Yuan YH. Ginsenoside rg1 plays a neuroprotective role in regulating the iron-regulated proteins and against lipid peroxidation in oligodendrocytes. Neurochem Res 2022;47(6):1721-35. https://doi.org/10.1007/s11064-022-03564-6. 
  23. Gudi V, Gingele S, Skripuletz T, Stangel M. Glial response during cuprizone-induced de- and remyelination in the cns: lessons learned. Front Cell Neurosci 2014;8:73. 
  24. Faizi M, Salimi A, Seydi E, Naserzadeh P, Kouhnavard M, Rahimi A, Pourahmad J. Toxicity of cuprizone a cu(2+) chelating agent on isolated mouse brain mitochondria: a justification for demyelination and subsequent behavioral dysfunction. Toxicol. Mech. Methods 2016;26:276-83.  https://doi.org/10.3109/15376516.2016.1172284
  25. Acs P, Kalman B. Pathogenesis of multiple sclerosis: what can we learn from the cuprizone model. Methods Mol Biol 2012;900:403-31.  https://doi.org/10.1007/978-1-60761-720-4_20
  26. Acs P, Ma Selak, Komoly S, Kalman B. Distribution of oligodendrocyte loss and mitochondrial toxicity in the cuprizone-induced experimental demyelination model. J Neuroimmunol 2013;262:128-31.  https://doi.org/10.1016/j.jneuroim.2013.06.012
  27. Kesterson JW, Carlton WW. Monoamine oxidase inhibition and the activity of other oxidative enzymes in the brains of mice fed cuprizone. Toxicol Appl Pharmacol 1971;20:386-95.  https://doi.org/10.1016/0041-008X(71)90281-X
  28. Venturini G. Enzymic activities and sodium, potassium and copper concentrations in mouse brain and liver after cuprizone treatment in vivo. J Neurochem 1973;21:1147-51.  https://doi.org/10.1111/j.1471-4159.1973.tb07569.x
  29. Benardais K, Kotsiari A, Skuljec J, Koutsoudaki PN, Gudi V, Singh V, Vulinovic F, Skripuletz T, Stangel M. Cuprizone [bis(cyclohexylidenehydrazide)] is selectively toxic for mature oligodendrocytes. Neurotox. Res. 2013;24:244-50.  https://doi.org/10.1007/s12640-013-9380-9
  30. Neumann B, Baror R, Zhao C, Segel M, Dietmann S, Rawji KS, Foerster S, McClain CR, Chalut K, Wijngaarden P, et al. Metformin restores cns remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell 2019;25:473-85. e8.  https://doi.org/10.1016/j.stem.2019.08.015
  31. Schoenfeld R, Wong A, Silva J, Li M, Itoh A, Horiuchi M, Itoh T, Pleasure D, Cortopassi G. Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation. Mitochondrion 2010;10:143-50.  https://doi.org/10.1016/j.mito.2009.12.141
  32. Naughton MC, McMahon JM, FitzGerald U. Differential activation of er stress pathways in myelinating cerebellar tracts. Int J Dev Neurosci 2015;47:347-60.  https://doi.org/10.1016/j.ijdevneu.2015.08.002
  33. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of bip and er stress transducers in the unfolded-protein response. Nat Cell Biol 2000;2:326-32.  https://doi.org/10.1038/35014014
  34. Choy MS, Yusoff P, Lee IC, Newton JC, Goh CW, Page R, Shenolikar S, Peti W. Structural and functional analysis of the gadd34:Pp1 eif2alpha phosphatase. Cell Rep. 2015;11:1885-91.  https://doi.org/10.1016/j.celrep.2015.05.043
  35. Li J, Inoue R, Togashi Y, Okuyama T, Satoh A, Kyohara M, Nishiyama K, Tsuno T, Miyashita D, Kin T, et al. Imeglimin ameliorates beta-cell apoptosis by modulating the endoplasmic reticulum homeostasis pathway. Diabetes 2022;71:424-39.  https://doi.org/10.2337/db21-0123
  36. Fischbach F, Nedelcu J, Leopold P, Zhan J, Clarner T, Nellessen L, Beibel C, Heuvel Y, Goswami A, Weis J, et al. Cuprizone-induced graded oligodendrocyte vulnerability is regulated by the transcription factor DNA damageinducible transcript 3. Glia 2019;67:263-76.  https://doi.org/10.1002/glia.23538
  37. Zheng QL, Zhu HY, Xu X, Chu SF, Cui LY, Dong YX, Liu Y, Zhan J, Wang Z, Chen N. Korean red ginseng alleviate depressive disorder by improving astrocyte gap junction function. J. Ethnopharmacol. 2021;281:114466. 
  38. Lee MJ, Jang M, Choi J, Chang BS, Kim DY, Kim SH, Kwak Y, Oh S, Lee J, Chang B, et al. Korean red ginseng and ginsenoside-rb1/-rg1 alleviate experimental autoimmune encephalomyelitis by suppressing th1 and th17 cells and upregulating regulatory t cells. Mol. Neurobiol. 2016;53:1977-2002.  https://doi.org/10.1007/s12035-015-9131-4
  39. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 2013;53:401-26.  https://doi.org/10.1146/annurev-pharmtox-011112-140320
  40. Ishibashi T, Dakin KA, Stevens B, Lee PR, Kozlov SV, Stewart CL, Fields RD. Astrocytes promote myelination in response to electrical impulses. Neuron 2006;49:823-32.  https://doi.org/10.1016/j.neuron.2006.02.006
  41. Dong YX, Chu SF, Wang SS, Tian YJ, He WB, Du YS, Wang Z, Yan X, Zhang Z, Chen N. Rg1 exerts protective effect in cpz-induced demyelination mouse model via inhibiting cxcl10-mediated glial response. Acta Pharmacol. Sin. 2022;43:563-76.  https://doi.org/10.1038/s41401-021-00696-3
  42. Powers BE, Sellers DL, Lovelett EA, Cheung W, Aalami SP, Zapertov N, Maris DO, Horner PJ. Remyelination reporter reveals prolonged refinement of spontaneously regenerated myelin. Proc. Natl. Acad. Sci. U.S.A. 2013;110:4075-80.  https://doi.org/10.1073/pnas.1210293110
  43. Najm FJ, Lager AM, Zaremba A, Wyatt K, Caprariello AV, Factor DC, Karl RT, Maeda T, Miler RH, Tesar PJ. Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nat. Biotechnol. 2013;31:426-33.  https://doi.org/10.1038/nbt.2561
  44. Groves AK, Barnett SC, Franklin RJ, Crang AJ, Mayer M, Blakemore WF, Noble M. Repair of demyelinated lesions by transplantation of purified o-2a progenitor cells. Nature 1993;362:453-5.  https://doi.org/10.1038/362453a0
  45. Windrem MS, Nunes MC, Rashbaum WK, Schwartz TH, Goodman RA, McKhann 2nd G, Roy NS, Goldman SA. Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nat. Med. 2004;10:93-7.  https://doi.org/10.1038/nm974
  46. Bujalka H, Koenning M, Jackson S, Perreau VM, Pope B, Hay CM, Mitew S, Hill AF, Lu QR, Wegner M, et al. Myrf is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biol. 2013;11:e1001625. 
  47. Pajares M, Cuadrado A, Rojo AI. Modulation of proteostasis by transcription factor nrf2 and impact in neurodegenerative diseases. Redox Biol 2017;11: 543-53.  https://doi.org/10.1016/j.redox.2017.01.006
  48. Cubillos-Ruiz JR, Bettigole SE, Glimcher LH. Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer. Cell 2017;168:692-706.  https://doi.org/10.1016/j.cell.2016.12.004
  49. Domingues HS, Portugal CC, Socodato R, Relvas JB. Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol 2016;4:71. 
  50. Traiffort E, Kassoussi A, Zahaf A, Laouarem Y. Astrocytes and microglia as major players of myelin production in normal and pathological conditions. Front Cell Neurosci 2020;14:79. 
  51. Luo JF, Shen XY, Lio CK, Dai Y, Cheng CS, Liu JX, Yao Y, Yu Y, Xie Y, Luo P, et al. Activation of nrf2/ho-1 pathway by nardochinoid c inhibits inflammation and oxidative stress in lipopolysaccharide-stimulated macrophages. Front Pharmacol. 2018;9:911. 
  52. Skripuletz T, Hackstette D, Bauer K, Gudi V, Pul R, Voss E, Berger K, Kipp M, Baumgartner W, Stangel M. Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain 2013;136:147-67.  https://doi.org/10.1093/brain/aws262
  53. Lloyd AF, Davies CL, Miron VE. Microglia: origins, homeostasis, and roles in myelin repair. Curr Opin Neurobiol 2017;47:113-20.  https://doi.org/10.1016/j.conb.2017.10.001
  54. Lee MJ, Chang BJ, Oh S, Nah SY, Cho IH. Korean red ginseng mitigates spinal demyelination in a model of acute multiple sclerosis by downregulating p38 mitogen-activated protein kinase and nuclear factor-kappab signaling pathways. J Ginseng Res 2018;42:436-46. https://doi.org/10.1016/j.jgr.2017.04.013