Advertisement

Journal of Molecular Medicine

, Volume 97, Issue 4, pp 463–472 | Cite as

Insight into the mechanism of action of dimethyl fumarate in multiple sclerosis

  • Sudhir Kumar Yadav
  • Devika Soin
  • Kouichi Ito
  • Suhayl Dhib-JalbutEmail author
Review
  • 451 Downloads

Abstract

Dimethyl fumarate (DMF) is an oral, disease-modifying agent for the treatment of relapsing–remitting multiple sclerosis (RRMS). However, details regarding its mode of action are still emerging. It is believed that the mode of action of DMF involves both nuclear factor erythroid-derived 2-related factor (Nrf2)–dependent and independent pathways, which lead to an anti-inflammatory immune response due to type II myeloid cell and Th2 cell differentiation and neuroprotection. In this review, we will focus on the molecular and signaling effects of DMF that lead to changes in peripheral immune cell composition and function, alteration in CNS cell-specific functions, and effect on the blood-brain barrier.

Keywords

Relapsing–remitting multiple sclerosis Dimethyl fumarate Nuclear factor erythroid-derived 2-related factor Immunomodulation Neuroprotection 

Notes

Acknowledgements

We would like to thank Tania Atanassova and Sasha Elizar for their critical comments on this review.

Compliance with ethical standards

Competing interests

S D-J received grant support from Teva Pharmaceuticals and Biogen Idec., and also serves as a consultant to TEVA, Bayer, Serono, Genentech and Genzyme. KI received financial support for research activities from Teva Pharmaceuticals and Biogen Idec.

References

  1. 1.
    Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367:1098–1107CrossRefGoogle Scholar
  2. 2.
    Werdenberg D, Joshi R, Wolffram S, Merkle HP, Langguth P (2003) Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters. Biopharm Drug Dispos 24:259–273CrossRefGoogle Scholar
  3. 3.
    Mrowietz U, Christophers E, Altmeyer P (1999) Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference. Br J Dermatol 141:424–429CrossRefGoogle Scholar
  4. 4.
    Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT, CONFIRM Study Investigators (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367:1087–1097CrossRefGoogle Scholar
  5. 5.
    Spencer CM, Crabtree-Hartman EC, Lehmann-Horn K, Cree BA, Zamvil SS (2015) Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2:e76CrossRefGoogle Scholar
  6. 6.
    Montes Diaz G, Fraussen J, Van Wijmeersch B, Hupperts R, Somers V (2018) Dimethyl fumarate induces a persistent change in the composition of the innate and adaptive immune system in multiple sclerosis patients. Sci Rep 8:8194CrossRefGoogle Scholar
  7. 7.
    Linker RA, Lee DH, Ryan S (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678–692CrossRefGoogle Scholar
  8. 8.
    Yukitake M (2018) Drug-induced progressive multifocal leukoencephalopathy in multiple sclerosis: a comprehensive review. Clin Exp Neuroimmunol 9(Suppl. 1):37–47CrossRefGoogle Scholar
  9. 9.
    Litjens NH, van Strijen E, van Gulpen C, Mattie H, van Dissel JT, Thio HB, Nibbering PH (2004) In vitro pharmacokinetics of anti-psoriatic fumaric acid esters. BMC Pharmacol 4:22CrossRefGoogle Scholar
  10. 10.
    Dibbert S, Clement B, Skak-Nielsen T, Mrowietz U, Rostami-Yazdi M (2013) Detection of fumarate-glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism. Arch Dermatol Res 305:447–451CrossRefGoogle Scholar
  11. 11.
    Mrowietz U, Morrison PJ, Suhrkamp I, Kumanova M, Clement B (2018) The pharmacokinetics of fumaric acid esters reveal their in vivo effects. Trends Pharmacol Sci 39:1–12CrossRefGoogle Scholar
  12. 12.
    Anton R, Haas M, Arlett P, Weise M, Balabanov P, Mazzaglia G, Prieto L, Keller-Stanislawski B, Raine J (2017) Drug-induced progressive multifocal leukoencephalopathy in multiple sclerosis: European regulators' perspective. Clin Pharmacol Ther 102:283–289CrossRefGoogle Scholar
  13. 13.
    Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, Spencer CM, Shetty A, Sagan SA, Cree BA, Sobel RA, Wipke BT, Steinman L et al (2016) Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proc Natl Acad Sci U S A 113:4777–4782CrossRefGoogle Scholar
  14. 14.
    Parodi B, Rossi S, Morando S, Cordano C, Bragoni A, Motta C, Usai C, Wipke BT, Scannevin RH, Mancardi GL, Centonze D, Kerlero de Rosbo N, Uccelli A (2015) Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS. Acta Neuropathol 130:279–295CrossRefGoogle Scholar
  15. 15.
    Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426CrossRefGoogle Scholar
  16. 16.
    Ryter SW, Alam J, Choi AM (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86:583–650CrossRefGoogle Scholar
  17. 17.
    Siegel D, Gustafson DL, Dehn DL, Han JY, Boonchoong P, Berliner LJ, Ross D (2004) NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol 65:1238–1247CrossRefGoogle Scholar
  18. 18.
    da Fonseca RR, Johnson WE, O'Brien SJ, Vasconcelos V, Antunes A (2010) Molecular evolution and the role of oxidative stress in the expansion and functional diversification of cytosolic glutathione transferases. BMC Evol Biol 10:281CrossRefGoogle Scholar
  19. 19.
    Hammer A, Waschbisch A, Kuhbandner K, Bayas A, Lee DH, Duscha A, Haghikia A, Gold R, Linker RA (2018) The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis. Ann Clin Transl Neurol 5:668–676CrossRefGoogle Scholar
  20. 20.
    Chen H, Assmann JC, Krenz A, Rahman M, Grimm M, Karsten CM, Kohl J, Offermanns S, Wettschureck N, Schwaninger M (2014) Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE. J Clin Invest 124:2188–2192CrossRefGoogle Scholar
  21. 21.
    Gillard GO, Collette B, Anderson J, Chao J, Scannevin RH, Huss DJ, Fontenot JD (2015) DMF, but not other fumarates, inhibits NF-kappaB activity in vitro in an Nrf2-independent manner. J Neuroimmunol 283:74–85CrossRefGoogle Scholar
  22. 22.
    Fiedler SE, Kerns AR, Tsang C, Tsang V, Bourdette D, Salinthone S (2016) Dimethyl fumarate activates the prostaglandin EP2 receptor and stimulates cAMP signaling in human peripheral blood mononuclear cells. Biochem Biophys Res Commun 475:19–24CrossRefGoogle Scholar
  23. 23.
    Aandahl EM, Moretto WJ, Haslett PA, Vang T, Bryn T, Tasken K, Nixon DF (2002) Inhibition of antigen-specific T cell proliferation and cytokine production by protein kinase A type I. J Immunol 169:802–808CrossRefGoogle Scholar
  24. 24.
    Diebold M, Sievers C, Bantug G, Sanderson N, Kappos L, Kuhle J, Lindberg RLP, Derfuss T (2018) Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis. J Autoimmun 86:39–50CrossRefGoogle Scholar
  25. 25.
    Longbrake EE, Ramsbottom MJ, Cantoni C, Ghezzi L, Cross AH, Piccio L (2016) Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients. Mult Scler 22:1061–1070CrossRefGoogle Scholar
  26. 26.
    Chaves C, Ganguly R, Ceresia C, Camac A (2017) Lymphocyte subtypes in relapsing-remitting multiple sclerosis patients treated with dimethyl fumarate. Mult Scler J Exp Transl Clin 3:2055217317702933Google Scholar
  27. 27.
    Longbrake EE, Cantoni C, Chahin S, Cignarella F, Cross AH, Piccio L (2018) Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count. Mult Scler 24:728–738CrossRefGoogle Scholar
  28. 28.
    Fleischer V, Friedrich M, Rezk A, Buhler U, Witsch E, Uphaus T, Bittner S, Groppa S, Tackenberg B, Bar-Or A et al (2018) Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS. Mult Scler 24:632–641CrossRefGoogle Scholar
  29. 29.
    Ghadiri M, Rezk A, Li R, Evans A, Luessi F, Zipp F, Giacomini PS, Antel J, Bar-Or A (2017) Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis. Neurol Neuroimmunol Neuroinflamm 4:e340CrossRefGoogle Scholar
  30. 30.
    Hoglund RA, Polak J, Vartdal F, Holmoy T, Lossius A (2018) B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate. Mult Scler Relat Disord 26:90–95CrossRefGoogle Scholar
  31. 31.
    Treumer F, Zhu K, Glaser R, Mrowietz U (2003) Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol 121:1383–1388CrossRefGoogle Scholar
  32. 32.
    Kornberg MD, Bhargava P, Kim PM, Putluri V, Snowman AM, Putluri N, Calabresi PA, Snyder SH (2018) Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360:449–453CrossRefGoogle Scholar
  33. 33.
    Clarkson BD, Walker A, Harris MG, Rayasam A, Sandor M, Fabry Z (2015) CCR2-dependent dendritic cell accumulation in the central nervous system during early effector experimental autoimmune encephalomyelitis is essential for effector T cell restimulation in situ and disease progression. J Immunol 194:531–541CrossRefGoogle Scholar
  34. 34.
    Peng H, Guerau-de-Arellano M, Mehta VB, Yang Y, Huss DJ, Papenfuss TL, Lovett-Racke AE, Racke MK (2012) Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor kappaB (NF-kappaB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem 287:28017–28026CrossRefGoogle Scholar
  35. 35.
    Ghoreschi K, Bruck J, Kellerer C, Deng C, Peng H, Rothfuss O, Hussain RZ, Gocke AR, Respa A, Glocova I et al (2011) Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med 208:2291–2303CrossRefGoogle Scholar
  36. 36.
    Zhu K, Mrowietz U (2001) Inhibition of dendritic cell differentiation by fumaric acid esters. J Invest Dermatol 116:203–208CrossRefGoogle Scholar
  37. 37.
    Litjens NH, Rademaker M, Ravensbergen B, Rea D, van der Plas MJ, Thio B, Walding A, van Dissel JT, Nibbering PH (2004) Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses. Eur J Immunol 34:565–575CrossRefGoogle Scholar
  38. 38.
    Croxford AL, Lanzinger M, Hartmann FJ, Schreiner B, Mair F, Pelczar P, Clausen BE, Jung S, Greter M, Becher B (2015) The cytokine GM-CSF drives the inflammatory signature of CCR2(+) monocytes and licenses autoimmunity. Immunity 43:502–514CrossRefGoogle Scholar
  39. 39.
    Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ et al (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218CrossRefGoogle Scholar
  40. 40.
    Han R, Xiao J, Zhai H, Hao J (2016) Dimethyl fumarate attenuates experimental autoimmune neuritis through the nuclear factor erythroid-derived 2-related factor 2/hemoxygenase-1 pathway by altering the balance of M1/M2 macrophages. J Neuroinflammation 13:97CrossRefGoogle Scholar
  41. 41.
    Michell-Robinson MA, Moore CS, Healy LM, Osso LA, Zorko N, Grouza V, Touil H, Poliquin-Lasnier L, Trudelle AM, Giacomini PS, Bar-Or A, Antel JP (2016) Effects of fumarates on circulating and CNS myeloid cells in multiple sclerosis. Ann Clin Transl Neurol 3:27–41CrossRefGoogle Scholar
  42. 42.
    Kurowska-Stolarska M, Alivernini S, Ballantine LE, Asquith DL, Millar NL, Gilchrist DS, Reilly J, Ierna M, Fraser AR, Stolarski B, McSharry C, Hueber AJ, Baxter D, Hunter J, Gay S, Liew FY, McInnes IB (2011) MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci U S A 108:11193–11198CrossRefGoogle Scholar
  43. 43.
    Schilling S, Goelz S, Linker R, Luehder F, Gold R (2006) Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol 145:101–107CrossRefGoogle Scholar
  44. 44.
    Cross SA, Cook DR, Chi AW, Vance PJ, Kolson LL, Wong BJ, Jordan-Sciutto KL, Kolson DL (2011) Dimethyl fumarate, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and macrophage-mediated neurotoxicity: a novel candidate for HIV neuroprotection. J Immunol 187:5015–5025CrossRefGoogle Scholar
  45. 45.
    Steinbach K, Piedavent M, Bauer S, Neumann JT, Friese MA (2013) Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs. J Immunol 191:4531–4539CrossRefGoogle Scholar
  46. 46.
    Rumble JM, Huber AK, Krishnamoorthy G, Srinivasan A, Giles DA, Zhang X, Wang L, Segal BM (2015) Neutrophil-related factors as biomarkers in EAE and MS. J Exp Med 212:23–35CrossRefGoogle Scholar
  47. 47.
    Naegele M, Tillack K, Reinhardt S, Schippling S, Martin R, Sospedra M (2012) Neutrophils in multiple sclerosis are characterized by a primed phenotype. J Neuroimmunol 242:60–71CrossRefGoogle Scholar
  48. 48.
    Kostic M, Dzopalic T, Zivanovic S, Zivkovic N, Cvetanovic A, Stojanovic I, Vojinovic S, Marjanovic G, Savic V, Colic M (2014) IL-17 and glutamate excitotoxicity in the pathogenesis of multiple sclerosis. Scand J Immunol 79:181–186CrossRefGoogle Scholar
  49. 49.
    Ishizu T, Osoegawa M, Mei FJ, Kikuchi H, Tanaka M, Takakura Y, Minohara M, Murai H, Mihara F, Taniwaki T, Kira JI (2005) Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain 128:988–1002CrossRefGoogle Scholar
  50. 50.
    Campbell SJ, Meier U, Mardiguian S, Jiang Y, Littleton ET, Bristow A, Relton J, Connor TJ, Anthony DC (2010) Sickness behaviour is induced by a peripheral CXC-chemokine also expressed in multiple sclerosis and EAE. Brain Behav Immun 24:738–746CrossRefGoogle Scholar
  51. 51.
    Muller S, Behnen M, Bieber K, Moller S, Hellberg L, Witte M, Hansel M, Zillikens D, Solbach W, Laskay T et al (2016) Dimethylfumarate impairs neutrophil functions. J Invest Dermatol 136:117–126CrossRefGoogle Scholar
  52. 52.
    Hoffmann JHO, Schaekel K, Hartl D, Enk AH, Hadaschik EN (2018) Dimethyl fumarate modulates neutrophil extracellular trap formation in a glutathione- and superoxide-dependent manner. Br J Dermatol 178:207–214CrossRefGoogle Scholar
  53. 53.
    Crome SQ, Lang PA, Lang KS, Ohashi PS (2013) Natural killer cells regulate diverse T cell responses. Trends Immunol 34:342–349CrossRefGoogle Scholar
  54. 54.
    Gross CC, Schulte-Mecklenbeck A, Runzi A, Kuhlmann T, Posevitz-Fejfar A, Schwab N, Schneider-Hohendorf T, Herich S, Held K, Konjevic M et al (2016) Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation. Proc Natl Acad Sci U S A 113:E2973–E2982CrossRefGoogle Scholar
  55. 55.
    Laroni A, Armentani E, Kerlero de Rosbo N, Ivaldi F, Marcenaro E, Sivori S, Gandhi R, Weiner HL, Moretta A, Mancardi GL, Uccelli A (2016) Dysregulation of regulatory CD56(bright) NK cells/T cells interactions in multiple sclerosis. J Autoimmun 72:8–18CrossRefGoogle Scholar
  56. 56.
    Medina S, Villarrubia N, Sainz de la Maza S, Lifante J, Costa-Frossard L, Roldan E, Picon C, Alvarez-Cermeno JC, Villar LM (2018) Optimal response to dimethyl fumarate associates in MS with a shift from an inflammatory to a tolerogenic blood cell profile. Mult Scler 24:1317–1327CrossRefGoogle Scholar
  57. 57.
    Smith MD, Calabresi PA, Bhargava P (2018) Dimethyl fumarate treatment alters NK cell function in multiple sclerosis. Eur J Immunol 48:380–383CrossRefGoogle Scholar
  58. 58.
    Al-Jaderi Z, Maghazachi AA (2015) Vitamin D(3) and monomethyl fumarate enhance natural killer cell lysis of dendritic cells and ameliorate the clinical score in mice suffering from experimental autoimmune encephalomyelitis. Toxins (Basel) 7:4730–4744CrossRefGoogle Scholar
  59. 59.
    Vego H, Sand KL, Hoglund RA, Fallang LE, Gundersen G, Holmoy T, Maghazachi AA (2016) Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a. Cell Mol Immunol 13:57–64CrossRefGoogle Scholar
  60. 60.
    Yadav SK, Mindur JE, Ito K, Dhib-Jalbut S (2015) Advances in the immunopathogenesis of multiple sclerosis. Curr Opin Neurol 28:206–219CrossRefGoogle Scholar
  61. 61.
    Blewett MM, Xie J, Zaro BW, Backus KM, Altman A, Teijaro JR, Cravatt BF (2016) Chemical proteomic map of dimethyl fumarate-sensitive cysteines in primary human T cells. Sci Signal 9:rs10CrossRefGoogle Scholar
  62. 62.
    Schneider A, Long SA, Cerosaletti K, Ni CT, Samuels P, Kita M, Buckner JH (2013) In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive T (regs) involves IL-6-mediated signaling. Sci Transl Med 5:170ra115CrossRefGoogle Scholar
  63. 63.
    Schloder J, Berges C, Luessi F, Jonuleit H (2017) Dimethyl fumarate therapy significantly improves the responsiveness of T cells in multiple sclerosis patients for immunoregulation by regulatory T cells. Int J Mol Sci 18:2Google Scholar
  64. 64.
    Gross CC, Schulte-Mecklenbeck A, Klinsing S, Posevitz-Fejfar A, Wiendl H, Klotz L (2016) Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 3:e183CrossRefGoogle Scholar
  65. 65.
    Wu Q, Wang Q, Mao G, Dowling CA, Lundy SK, Mao-Draayer Y (2017) Dimethyl fumarate selectively reduces memory T cells and shifts the balance between Th1/Th17 and Th2 in multiple sclerosis patients. J Immunol 198:3069–3080CrossRefGoogle Scholar
  66. 66.
    Tahvili S, Zandieh B, Amirghofran Z (2015) The effect of dimethyl fumarate on gene expression and the level of cytokines related to different T helper cell subsets in peripheral blood mononuclear cells of patients with psoriasis. Int J Dermatol 54:e254–e260CrossRefGoogle Scholar
  67. 67.
    Lundy SK, Wu Q, Wang Q, Dowling CA, Taitano SH, Mao G, Mao-Draayer Y (2016) Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets. Neurol Neuroimmunol Neuroinflamm 3:e211CrossRefGoogle Scholar
  68. 68.
    Li R, Rezk A, Ghadiri M, Luessi F, Zipp F, Li H, Giacomini PS, Antel J, Bar-Or A (2017) Dimethyl fumarate treatment mediates an anti-inflammatory shift in B cell subsets of patients with multiple sclerosis. J Immunol 198:691–698CrossRefGoogle Scholar
  69. 69.
    Mathias A, Perriot S, Canales M, Blatti C, Gaubicher C, Schluep M, Engelhardt B, Du Pasquier R (2017) Impaired T-cell migration to the CNS under fingolimod and dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 4:e401CrossRefGoogle Scholar
  70. 70.
    Kihara Y, Groves A, Rivera RR, Chun J (2015) Dimethyl fumarate inhibits integrin alpha4 expression in multiple sclerosis models. Ann Clin Transl Neurol 2:978–983CrossRefGoogle Scholar
  71. 71.
    Dehmel T, Dobert M, Pankratz S, Leussink VI, Hartung HP, Wiendl H, Kieseier BC (2014) Monomethylfumarate reduces in vitro migration of mononuclear cells. Neurol Sci 35:1121–1125CrossRefGoogle Scholar
  72. 72.
    Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15:545–558CrossRefGoogle Scholar
  73. 73.
    Campolo M, Casili G, Biundo F, Crupi R, Cordaro M, Cuzzocrea S, Esposito E (2017) The neuroprotective effect of dimethyl fumarate in an MPTP-mouse model of Parkinson's disease: involvement of reactive oxygen species/nuclear factor-kappaB/nuclear transcription factor related to NF-E2. Antioxid Redox Signal 27:453–471CrossRefGoogle Scholar
  74. 74.
    Lin R, Cai J, Kostuk EW, Rosenwasser R, Iacovitti L (2016) Fumarate modulates the immune/inflammatory response and rescues nerve cells and neurological function after stroke in rats. J Neuroinflammation 13:269CrossRefGoogle Scholar
  75. 75.
    Wang Q, Chuikov S, Taitano S, Wu Q, Rastogi A, Tuck SJ, Corey JM, Lundy SK, Mao-Draayer Y (2015) Dimethyl fumarate protects neural stem/progenitor cells and neurons from oxidative damage through Nrf2-ERK1/2 MAPK pathway. Int J Mol Sci 16:13885–13907CrossRefGoogle Scholar
  76. 76.
    Vartanian T, Li Y, Zhao M, Stefansson K (1995) Interferon-gamma-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis. Mol Med 1:732–743CrossRefGoogle Scholar
  77. 77.
    Iglesias A, Bauer J, Litzenburger T, Schubart A, Linington C (2001) T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis. Glia 36:220–234CrossRefGoogle Scholar
  78. 78.
    Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717CrossRefGoogle Scholar
  79. 79.
    Huang H, Taraboletti A, Shriver LP (2015) Dimethyl fumarate modulates antioxidant and lipid metabolism in oligodendrocytes. Redox Biol 5:169–175CrossRefGoogle Scholar
  80. 80.
    Zarrouk A, Nury T, Karym EM, Vejux A, Sghaier R, Gondcaille C, Andreoletti P, Trompier D, Savary S, Cherkaoui-Malki M, Debbabi M, Fromont A, Riedinger JM, Moreau T, Lizard G (2017) Attenuation of 7-ketocholesterol-induced overproduction of reactive oxygen species, apoptosis, and autophagy by dimethyl fumarate on 158N murine oligodendrocytes. J Steroid Biochem Mol Biol 169:29–38CrossRefGoogle Scholar
  81. 81.
    Galloway DA, Williams JB, Moore CS (2017) Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation. Ann Clin Transl Neurol 4:381–391CrossRefGoogle Scholar
  82. 82.
    Lin SX, Lisi L, Dello Russo C, Polak PE, Sharp A, Weinberg G, Kalinin S, Feinstein DL (2011) The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro 3:2CrossRefGoogle Scholar
  83. 83.
    Kalinin S, Polak PE, Lin SX, Braun D, Guizzetti M, Zhang X, Rubinstein I, Feinstein DL (2013) Dimethyl fumarate regulates histone deacetylase expression in astrocytes. J Neuroimmunol 263:13–19CrossRefGoogle Scholar
  84. 84.
    Metz I, Traffehn S, Strassburger-Krogias K, Keyvani K, Bergmann M, Nolte K, Weber MS, Bartsch T, Gold R, Bruck W (2015) Glial cells express nuclear nrf2 after fumarate treatment for multiple sclerosis and psoriasis. Neurol Neuroimmunol Neuroinflamm 2:e99CrossRefGoogle Scholar
  85. 85.
    Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, Mahad D, Bradl M, van Horssen J, Lassmann H (2012) NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 135:886–899CrossRefGoogle Scholar
  86. 86.
    Peng H, Li H, Sheehy A, Cullen P, Allaire N, Scannevin RH (2016) Dimethyl fumarate alters microglia phenotype and protects neurons against proinflammatory toxic microenvironments. J Neuroimmunol 299:35–44CrossRefGoogle Scholar
  87. 87.
    Wilms H, Sievers J, Rickert U, Rostami-Yazdi M, Mrowietz U, Lucius R (2010) Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1beta, TNF-alpha and IL-6 in an in-vitro model of brain inflammation. J Neuroinflammation 7:30CrossRefGoogle Scholar
  88. 88.
    Kunze R, Urrutia A, Hoffmann A, Liu H, Helluy X, Pham M, Reischl S, Korff T, Marti HH (2015) Dimethyl fumarate attenuates cerebral edema formation by protecting the blood-brain barrier integrity. Exp Neurol 266:99–111CrossRefGoogle Scholar
  89. 89.
    Lim JL, van der Pol SM, Di Dio F, van Het Hof B, Kooij G, de Vries HE, van Horssen J (2016) Protective effects of monomethyl fumarate at the inflamed blood-brain barrier. Microvasc Res 105:61–69CrossRefGoogle Scholar
  90. 90.
    Benardais K, Pul R, Singh V, Skripuletz T, Lee DH, Linker RA, Gudi V, Stangel M (2013) Effects of fumaric acid esters on blood-brain barrier tight junction proteins. Neurosci Lett 555:165–170CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sudhir Kumar Yadav
    • 1
  • Devika Soin
    • 1
  • Kouichi Ito
    • 1
  • Suhayl Dhib-Jalbut
    • 1
    Email author
  1. 1.Department of NeurologyRutgers–Robert Wood Johnson Medical SchoolPiscatawayUSA

Personalised recommendations