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Transcriptional Regulation of Brain-Derived Neurotrophic Factor (BDNF) by Methyl CpG Binding Protein 2 (MeCP2): a Novel Mechanism for Re-Myelination and/or Myelin Repair Involved in the Treatment of Multiple Sclerosis (MS)

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Abstract

Multiple sclerosis (MS) is a chronic progressive, neurological disease characterized by the targeted immune system-mediated destruction of central nervous system (CNS) myelin. Autoreactive CD4+ T helper cells have a key role in orchestrating MS-induced myelin damage. Once activated, circulating Th1-cells secrete a variety of inflammatory cytokines that foster the breakdown of blood–brain barrier (BBB) eventually infiltrating into the CNS. Inside the CNS, they become reactivated upon exposure to the myelin structural proteins and continue to produce inflammatory cytokines such as tumor necrosis factor α (TNFα) that leads to direct activation of antibodies and macrophages that are involved in the phagocytosis of myelin. Proliferating oligodendrocyte precursors (OPs) migrating to the lesion sites are capable of acute remyelination but unable to completely repair or restore the immune system-mediated myelin damage. This results in various permanent clinical neurological disabilities such as cognitive dysfunction, fatigue, bowel/bladder abnormalities, and neuropathic pain. At present, there is no cure for MS. Recent remyelination and/or myelin repair strategies have focused on the role of the neurotrophin brain-derived neurotrophic factor (BDNF) and its upstream transcriptional repressor methyl CpG binding protein (MeCP2). Research in the field of epigenetic therapeutics involving histone deacetylase (HDAC) inhibitors and lysine acetyl transferase (KAT) inhibitors is being explored to repress the detrimental effects of MeCP2. This review will address the role of MeCP2 and BDNF in remyelination and/or myelin repair and the potential of HDAC and KAT inhibitors as novel therapeutic interventions for MS.

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References

  1. Janssens AC, van Doorn PA, de Boer JB, van der Meche FG, Passchier J, Hintzen RQ (2003) Impact of recently diagnosed multiple sclerosis on quality of life, anxiety, depression and distress of patients and partners. Acta Neurol Scand 108(6):389–395

    Article  PubMed  CAS  Google Scholar 

  2. Gold R, Montalban X (2012) Multiple sclerosis: more pieces of the immunological puzzle. Lancet Neurol 11(1):9–10

    Article  PubMed  Google Scholar 

  3. Namaka M, Turcotte D, Leong C, Grossberndt A, Klassen D (2008) Multiple sclerosis: etiology and treatment strategies. Consult Pharm 23(11):886–896

    Article  PubMed  Google Scholar 

  4. Batoulis H, Addicks K, Kuerten S (2010) Emerging concepts in autoimmune encephalomyelitis beyond the CD4/T(H)1 paradigm. Ann Anat Ana Anz Off Organ Anat Ges 192(4):179–193

    Article  CAS  Google Scholar 

  5. Korn T, Mitsdoerffer M, Kuchroo VK (2010) Immunological basis for the development of tissue inflammation and organ-specific autoimmunity in animal models of multiple sclerosis. Results Probl Cell Differ 51:43–74

    Article  PubMed  CAS  Google Scholar 

  6. Merrill JE (1992) Proinflammatory and antiinflammatory cytokines in multiple sclerosis and central nervous system acquired immunodeficiency syndrome. J Immunother 1991 12(3):167–170

    PubMed  CAS  Google Scholar 

  7. Segal BM, Cross AH (2000) Fas(t) track to apoptosis in MS: TNF receptors may suppress or potentiate CNS demyelination. Neurology 55(7):906–907

    Article  PubMed  CAS  Google Scholar 

  8. Zeis T, Graumann U, Reynolds R, Schaeren-Wiemers N (2008) Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection. Brain 131(1):288–303

    Article  PubMed  Google Scholar 

  9. Hauser SL, Oksenberg JR (2006) The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52(1):61–76

    Article  PubMed  CAS  Google Scholar 

  10. Melanson M, Miao P, Eisenstat D, Gong Y, Gu X, Au K et al (2009) Experimental autoimmune encephalomyelitis-induced upregulation of tumor necrosis factor-alpha in the dorsal root ganglia. Mult Scler 15(10):1135–1145

    Article  PubMed  CAS  Google Scholar 

  11. Codarri L, Fontana A, Becher B (2010) Cytokine networks in multiple sclerosis: lost in translation. Curr Opin Neurol 23(3):205–211

    Article  PubMed  CAS  Google Scholar 

  12. Glabinski AR, Bielecki B, Kawczak JA, Tuohy VK, Selmaj K, Ransohoff RM (2004) Treatment with soluble tumor necrosis factor receptor (sTNFR):Fc/p80 fusion protein ameliorates relapsing-remitting experimental autoimmune encephalomyelitis and decreases chemokine expression. Autoimmunity 37(6–7):465–471

    Article  PubMed  CAS  Google Scholar 

  13. Mills RJ, Yap L, Young CA (2007) Treatment for ataxia in multiple sclerosis. The Cochrane database of systematic reviews. (1):CD005029

  14. Namaka M, Leong C, Grossberndt A, Klowak M, Turcotte D, Esfahani F et al (2009) A treatment algorithm for neuropathic pain: an update. Consult Pharm 24(12):885–902

    Article  PubMed  Google Scholar 

  15. Beard S, Hunn A, Wight J (2003) Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess 7(40):iii, ix-x, 1–111

  16. Melanson M, Grossberndt A, Klowak M, Leong C, Frost EE, Prout M et al (2010) Fatigue and cognition in patients with relapsing multiple sclerosis treated with interferon beta. Int J Neurosci 120(10):631–640

    Article  PubMed  CAS  Google Scholar 

  17. Wingerchuk DM, Carter JL (2014) Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 89(2):225–240

    Article  PubMed  Google Scholar 

  18. Lopez-Diego RS, Weiner HL (2008) Novel therapeutic strategies for multiple sclerosis–a multifaceted adversary. Nat Rev Drug Discov 7(11):909–925

    Article  PubMed  CAS  Google Scholar 

  19. Lim SY, Constantinescu CS (2010) Current and future disease-modifying therapies in multiple sclerosis. Int J Clin Pract 64(5):637–650

    Article  PubMed  CAS  Google Scholar 

  20. Fernandez O, Arnal-Garcia C, Arroyo-Gonzalez R, Brieva L, Calles-Hernandez MC, Casanova-Estruch B et al (2013) Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (III). Rev Neurol 57(7):317–329

    PubMed  Google Scholar 

  21. Keough MB, Yong VW (2013) Remyelination therapy for multiple sclerosis. Neurother J Am Soc Exp Neurother 10(1):44–54

    Article  CAS  Google Scholar 

  22. Hagemeier K, Bruck W, Kuhlmann T (2012) Multiple sclerosis - remyelination failure as a cause of disease progression. Histol Histopathol 27(3):277–287

    PubMed  CAS  Google Scholar 

  23. Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21(3):381–395

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359):214–219

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Niino M, Fukazawa T, Kikuchi S, Sasaki H (2008) Therapeutic potential of vitamin D for multiple sclerosis. Curr Med Chem 15(5):499–505

    Article  PubMed  CAS  Google Scholar 

  26. Pakpoor J, Giovannoni G, Ramagopalan SV (2013) Epstein-Barr virus and multiple sclerosis: association or causation? Expert Rev Neurother 13(3):287–297

    Article  PubMed  CAS  Google Scholar 

  27. Kurtzke JF (2005) Epidemiology and etiology of multiple sclerosis. Phys Med Rehabil Clin N Am 16(2):327–349

    Article  PubMed  Google Scholar 

  28. Koch MW, Metz LM, Kovalchuk O (2013) Epigenetic changes in patients with multiple sclerosis. Nat Rev Neurol 9(1):35–43

    Article  PubMed  CAS  Google Scholar 

  29. Koch CM, Wagner W (2013) Epigenetic biomarker to determine replicative senescence of cultured cells. Methods Mol Biol 1048:309–321

    Article  PubMed  CAS  Google Scholar 

  30. Ramagopalan SV, Dobson R, Meier UC, Giovannoni G (2010) Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol 9(7):727–739

    Article  PubMed  Google Scholar 

  31. Niller HH, Wolf H, Ay E, Minarovits J (2011) Epigenetic dysregulation of epstein-barr virus latency and development of autoimmune disease. Adv Exp Med Biol 711:82–102

    Article  PubMed  CAS  Google Scholar 

  32. Pereira F, Barbachano A, Singh PK, Campbell MJ, Munoz A, Larriba MJ (2012) Vitamin D has wide regulatory effects on histone demethylase genes. Cell Cycle 11(6):1081–1089

    Article  PubMed  CAS  Google Scholar 

  33. Guan H, Nagarkatti PS, Nagarkatti M (2011) CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis. J Immunol 186(12):6955–6964

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  34. Ma J, Wang R, Fang X, Ding Y, Sun Z (2011) Critical role of TCF-1 in repression of the IL-17 gene. PLoS One 6(9):e24768

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Meehan RR, Lewis JD, McKay S, Kleiner EL, Bird AP (1989) Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58(3):499–507

    Article  PubMed  CAS  Google Scholar 

  36. Lewis JD, Meehan RR, Henzel WJ, Maurer-Fogy I, Jeppesen P, Klein F et al (1992) Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69(6):905–914

    Article  PubMed  CAS  Google Scholar 

  37. Mnatzakanian GN, Lohi H, Munteanu I, Alfred SE, Yamada T, MacLeod PJ et al (2004) A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat Genet 36(4):339–341

    Article  PubMed  CAS  Google Scholar 

  38. Kriaucionis S, Bird A (2004) The major form of MeCP2 has a novel N-terminus generated by alternative splicing. Nucleic Acids Res 32(5):1818–1823

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  39. Nan X, Campoy FJ, Bird A (1997) MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88(4):471–481

    Article  PubMed  CAS  Google Scholar 

  40. Zachariah RM, Rastegar M (2012) Linking epigenetics to human disease and Rett syndrome: the emerging novel and challenging concepts in MeCP2 research. Neural Plast 2012:415825

    PubMed Central  PubMed  Google Scholar 

  41. Olson CO, Zachariah RM, Ezeonwuka CD, Liyanage VR, Rastegar M (2014) Brain region-specific expression of MeCP2 isoforms correlates with DNA methylation within Mecp2 regulatory elements. PLoS One 9(3):e90645

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  42. Dragich JM, Kim YH, Arnold AP, Schanen NC (2007) Differential distribution of the MeCP2 splice variants in the postnatal mouse brain. J Comp Neurol 501(4):526–542

    Article  PubMed  Google Scholar 

  43. Zachariah RM, Olson CO, Ezeonwuka C, Rastegar M (2012) Novel MeCP2 isoform-specific antibody reveals the endogenous MeCP2E1 expression in murine brain, primary neurons and astrocytes. PLoS One 7(11):e49763

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Kerr B, Soto CJ, Saez M, Abrams A, Walz K, Young JI (2012) Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes. Eur Journal Hum Genet EJHG 20(1):69–76

    Article  PubMed  CAS  Google Scholar 

  45. Rastegar M, Hotta A, Pasceri P, Makarem M, Cheung AY, Elliott S et al (2009) MECP2 isoform-specific vectors with regulated expression for Rett syndrome gene therapy. PLoS One 4(8):e6810

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  46. Cusack SM, Rohn TT, Medeck RJ, Irwin KM, Brown RJ, Mercer LM et al (2004) Suppression of MeCP2beta expression inhibits neurite extension in PC12 cells. Exp Cell Res 299(2):442–453

    Article  PubMed  CAS  Google Scholar 

  47. Dastidar SG, Bardai FH, Ma C, Price V, Rawat V, Verma P et al (2012) Isoform-specific toxicity of Mecp2 in postmitotic neurons: suppression of neurotoxicity by FoxG1. J Neurosci Off J Soc Neurosci 32(8):2846–2855

    Article  CAS  Google Scholar 

  48. Liyanage VR, Zachariah RM, Rastegar M (2013) Decitabine alters the expression of Mecp2 isoforms via dynamic DNA methylation at the Mecp2 regulatory elements in neural stem cells. Mol Autism 4(1):46

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  49. Sheikh TI, Mittal K, Willis MJ, Vincent JB (2013) A synonymous change, p.Gly16Gly in MECP2 Exon 1, causes a cryptic splice event in a Rett syndrome patient. Orphanet J Rare Dis 8:108

    Article  PubMed Central  PubMed  Google Scholar 

  50. Saxena A, de Lagarde D, Leonard H, Williamson SL, Vasudevan V, Christodoulou J et al (2006) Lost in translation: translational interference from a recurrent mutation in exon 1 of MECP2. J Med Genet 43(6):470–477

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  51. Meehan RR, Lewis JD, Bird AP (1992) Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res 20(19):5085–5092

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  52. Na ES, Monteggia LM (2011) The role of MeCP2 in CNS development and function. Horm Behav 59(3):364–368

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  53. Vora P, Mina R, Namaka M, Frost EE (2010) A novel transcriptional regulator of myelin gene expression: implications for neurodevelopmental disorders. Neuroreport 21(14):917–921

    Article  PubMed  CAS  Google Scholar 

  54. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN et al (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393(6683):386–389

    Article  PubMed  CAS  Google Scholar 

  55. Wade PA, Jones PL, Vermaak D, Veenstra GJ, Imhof A, Sera T et al (1998) Histone deacetylase directs the dominant silencing of transcription in chromatin: association with MeCP2 and the Mi-2 chromodomain SWI/SNF ATPase. Cold Spring Harb Symp Quant Biol 63:435–445

    Article  PubMed  CAS  Google Scholar 

  56. Nan X, Cross S, Bird A (1998) Gene silencing by methyl-CpG-binding proteins. Novartis Found Symp 214:6–16, discussion −21, 46–50

    PubMed  CAS  Google Scholar 

  57. Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N et al (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19(2):187–191

    Article  PubMed  CAS  Google Scholar 

  58. Yu F, Thiesen J, Stratling WH (2000) Histone deacetylase-independent transcriptional repression by methyl-CpG-binding protein 2. Nucleic Acids Res 28(10):2201–2206

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  59. Yakabe S, Soejima H, Yatsuki H, Tominaga H, Zhao W, Higashimoto K et al (2008) MeCP2 knockdown reveals DNA methylation-independent gene repression of target genes in living cells and a bias in the cellular location of target gene products. Genes Genet Syst 83(2):199–208

    Article  PubMed  CAS  Google Scholar 

  60. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC et al (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302(5646):885–889

    Article  PubMed  CAS  Google Scholar 

  61. Chang Q, Khare G, Dani V, Nelson S, Jaenisch R (2006) The disease progression of mecp2 mutant mice is affected by the level of BDNF expression. Neuron 49(3):341–348

    Article  PubMed  CAS  Google Scholar 

  62. Acosta CM, Cortes C, MacPhee H, Namaka MP (2013) Exploring the role of nerve growth factor in multiple sclerosis: implications in myelin repair. CNS Neurol Disord Drug Targets 12(8):1242–1256

    Article  PubMed  CAS  Google Scholar 

  63. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23(2):185–188

    Article  PubMed  CAS  Google Scholar 

  64. Couvert P, Bienvenu T, Aquaviva C, Poirier K, Moraine C, Gendrot C et al (2001) MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet 10(9):941–946

    Article  PubMed  CAS  Google Scholar 

  65. Nagarajan RP, Hogart AR, Gwye Y, Martin MR, LaSalle JM (2006) Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics 1(4):e1–e11

    Article  PubMed Central  PubMed  Google Scholar 

  66. Lam CW, Yeung WL, Ko CH, Poon PM, Tong SF, Chan KY et al (2000) Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome. J Med Genet 37(12):E41

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Miao CG, Huang C, Huang Y, Yang YY, He X, Zhang L et al (2013) MeCP2 modulates the canonical Wnt pathway activation by targeting SFRP4 in rheumatoid arthritis fibroblast-like synoviocytes in rats. Cell Signal 25(3):598–608

    Article  PubMed  CAS  Google Scholar 

  68. Delcuve GP, Rastegar M, Davie JR (2009) Epigenetic control. J Cell Physiol 219(2):243–250

    Article  PubMed  CAS  Google Scholar 

  69. Ellis J, Hotta A, Rastegar M (2007) Retrovirus silencing by an epigenetic TRIM. Cell 131(1):13–14

    Article  PubMed  CAS  Google Scholar 

  70. Liyanage VR, Zachariah RM, Delcuve GP, Davie JR, Rastegar M (2012) New developments in chromatin research: An epigenetic perspective. In: Simpson NM, Stewart VJ (eds) New Developments in Chromatin Research:1: Nova Science Publishers, Inc

  71. Barber BA, Rastegar M (2010) Epigenetic control of Hox genes during neurogenesis, development, and disease. Ann Anat Anat Anz Off Organ Anat Ges 192(5):261–274

    Article  CAS  Google Scholar 

  72. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047):1300–1303

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  73. Jabbari K, Bernardi G (2004) Cytosine methylation and CpG, TpG (CpA) and TpA frequencies. Gene 333:143–149

    Article  PubMed  CAS  Google Scholar 

  74. Mellen M, Ayata P, Dewell S, Kriaucionis S, Heintz N (2012) MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151(7):1417–1430

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  75. Zachariah RM, Rastegar M (2012) Linking epigenetics to human disease and Rett syndrome: the emerging novel and challenging concepts in MeCP2 research. Neural Plast 2012:10

    Google Scholar 

  76. Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J et al (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320(5880):1224–1229

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  77. Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B et al (2014) Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci 17(2):215–222

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  78. Pedre X, Mastronardi F, Bruck W, Lopez-Rodas G, Kuhlmann T, Casaccia P (2011) Changed histone acetylation patterns in normal-appearing white matter and early multiple sclerosis lesions. J Neurosci Off J Soc Neurosci 31(9):3435–3445

    Article  CAS  Google Scholar 

  79. Yang H, Lee SM, Gao B, Zhang J, Fang D (2013) Histone deacetylase sirtuin 1 deacetylates IRF1 protein and programs dendritic cells to control Th17 protein differentiation during autoimmune inflammation. J Biol Chem 288(52):37256–37266

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  80. Kumagai C, Kalman B, Middleton FA, Vyshkina T, Massa PT (2012) Increased promoter methylation of the immune regulatory gene SHP-1 in leukocytes of multiple sclerosis subjects. J Neuroimmunol 246(1–2):51–57

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  81. Kremer D, Schichel T, Forster M, Tzekova N, Bernard C, van der Valk P et al (2013) Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann Neurol 74(5):721–732

    Article  PubMed  CAS  Google Scholar 

  82. Perron H, Lang A (2010) The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation. Clin Rev Allergy Immunol 39(1):51–61

    Article  PubMed  CAS  Google Scholar 

  83. Kim JK, Samaranayake M, Pradhan S (2009) Epigenetic mechanisms in mammals. Cell Mol Life Sci CMLS 66(4):596–612

    Article  PubMed  CAS  Google Scholar 

  84. Faraco G, Cavone L, Chiarugi A (2011) The therapeutic potential of HDAC inhibitors in the treatment of multiple sclerosis. Mol Med 17(5–6):442–447

    PubMed Central  PubMed  CAS  Google Scholar 

  85. Camelo S, Iglesias AH, Hwang D, Due B, Ryu H, Smith K et al (2005) Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol 164(1–2):10–21

    Article  PubMed  CAS  Google Scholar 

  86. Zhang Z, Zhang ZY, Wu Y, Schluesener HJ (2012) Valproic acid ameliorates inflammation in experimental autoimmune encephalomyelitis rats. Neuroscience 221:140–150

    Article  PubMed  CAS  Google Scholar 

  87. Pazhoohan S, Satarian L, Asghari AA, Salimi M, Kiani S, Mani AR et al (2014) Valproic Acid attenuates disease symptoms and increases endogenous myelin repair by recruiting neural stem cells and oligodendrocyte progenitors in experimental autoimmune encephalomyelitis. Neuro Degener Dis 13(1):45–52

    CAS  Google Scholar 

  88. Ge Z, Da Y, Xue Z, Zhang K, Zhuang H, Peng M et al (2013) Vorinostat, a histone deacetylase inhibitor, suppresses dendritic cell function and ameliorates experimental autoimmune encephalomyelitis. Exp Neurol 241:56–66

    Article  PubMed  CAS  Google Scholar 

  89. Kanakasabai S, Casalini E, Walline CC, Mo C, Chearwae W, Bright JJ (2012) Differential regulation of CD4(+) T helper cell responses by curcumin in experimental autoimmune encephalomyelitis. J Nutr Biochem 23(11):1498–1507

    Article  PubMed  CAS  Google Scholar 

  90. Manikandan R, Beulaja M, Thiagarajan R, Priyadarsini A, Saravanan R, Arumugam M (2011) Ameliorative effects of curcumin against renal injuries mediated by inducible nitric oxide synthase and nuclear factor kappa B during gentamicin-induced toxicity in Wistar rats. Eur J Pharmacol 670(2–3):578–585

    Article  PubMed  CAS  Google Scholar 

  91. Xie L, Li XK, Funeshima-Fuji N, Kimura H, Matsumoto Y, Isaka Y et al (2009) Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production. Int Immunopharmacol 9(5):575–581

    Article  PubMed  CAS  Google Scholar 

  92. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y et al (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302(5646):890–893

    Article  PubMed  CAS  Google Scholar 

  93. Zhu W, Frost EE, Begum F, Vora P, Au K, Gong Y et al (2012) The role of dorsal root ganglia activation and brain-derived neurotrophic factor in multiple sclerosis. J Cell Mol Med 16(8):1856–1865

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  94. Begum F, Zhu W, Cortes C, Macneil B, Namaka M (2013) Elevation of tumor necrosis factor alpha in dorsal root ganglia and spinal cord is associated with neuroimmune modulation of pain in an animal model of multiple sclerosis. J Neuroimmune Pharmacol Off J Soc NeuroImmune Pharmacol 8(3):677–690

    Article  CAS  Google Scholar 

  95. Saha R, Liu X, Pahan K (2006) Up-regulation of BDNF in astrocytes by TNF-α: a case for the neuroprotective role of cytokine. J Neuroimmune Pharmacol 1(3):212–222

    Article  PubMed Central  PubMed  Google Scholar 

  96. Aloe L, Properzi F, Probert L, Akassoglou K, Kassiotis G, Micera A et al (1999) Learning abilities, NGF and BDNF brain levels in two lines of TNF-alpha transgenic mice, one characterized by neurological disorders, the other phenotypically normal. Brain Res 840(1–2):125–137

    Article  PubMed  CAS  Google Scholar 

  97. Kuno R, Yoshida Y, Nitta A, Nabeshima T, Wang J, Sonobe Y et al (2006) The role of TNF-alpha and its receptors in the production of NGF and GDNF by astrocytes. Brain Res 1116(1):12–18

    Article  PubMed  CAS  Google Scholar 

  98. Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J (1994) Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience 62(2):327–331

    Article  PubMed  CAS  Google Scholar 

  99. Katz DM (2014) Brain-derived neurotrophic factor and rett syndrome. Handb Exp Pharmacol 220:481–495

    Article  PubMed  CAS  Google Scholar 

  100. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S et al (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306(5695):487–491

    Article  PubMed  CAS  Google Scholar 

  101. Kolbeck R, Jungbluth S, Barde YA (1994) Characterisation of neurotrophin dimers and monomers. Eur J Biochem 225(3):995–1003

    Article  PubMed  CAS  Google Scholar 

  102. Seidah NG, Benjannet S, Pareek S, Chretien M, Murphy RA (1996) Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett 379(3):247–250

    Article  PubMed  CAS  Google Scholar 

  103. Bibel M, Hoppe E, Barde YA (1999) Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR. EMBO J 18(3):616–622

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  104. Patapoutian A, Reichardt LF (2001) Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol 11(3):272–280

    Article  PubMed  CAS  Google Scholar 

  105. Lee FS, Kim AH, Khursigara G, Chao MV (2001) The uniqueness of being a neurotrophin receptor. Curr Opin Neurobiol 11(3):281–286

    Article  PubMed  CAS  Google Scholar 

  106. Binder DK, Scharfman HE (2004) Brain-derived neurotrophic factor. Growth Factors 22(3):123–131

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  107. Schecterson LC, Bothwell M (2010) Neurotrophin receptors: old friends with new partners. Dev Neurobiol 70(5):332–338

    PubMed  CAS  Google Scholar 

  108. Shamovsky IL, Ross GM, Riopelle RJ, Weaver DF (1999) The interaction of neurotrophins with the p75NTR common neurotrophin receptor: a comprehensive molecular modeling study. Protein Sci 8(11):2223–2233

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  109. Chen Y, Zeng J, Cen L, Chen Y, Wang X, Yao G et al (2009) Multiple roles of the p75 neurotrophin receptor in the nervous system. J Int Med Res 37(2):281–288

    Article  PubMed  CAS  Google Scholar 

  110. Cosgaya JM, Chan JR, Shooter EM (2002) The neurotrophin receptor p75NTR as a positive modulator of myelination. Science 298(5596):1245–1248

    Article  PubMed  CAS  Google Scholar 

  111. Keita M, Magy L, Heape A, Richard L, Piaser M, Vallat JM (2002) Immunocytological studies of L-MAG expression regulation during myelination of embryonic brain cell cocultures. Dev Neurosci 24(6):495–503

    Article  PubMed  CAS  Google Scholar 

  112. Tomita K, Kubo T, Matsuda K, Fujiwara T, Yano K, Winograd JM et al (2007) The neurotrophin receptor p75NTR in Schwann cells is implicated in remyelination and motor recovery after peripheral nerve injury. Glia 55(11):1199–1208

    Article  PubMed  Google Scholar 

  113. Althaus HH, Kloppner S, Klopfleisch S, Schmitz M (2008) Oligodendroglial cells and neurotrophins: a polyphonic cantata in major and minor. J Mol Neurosci 35(1):65–79

    Article  PubMed  CAS  Google Scholar 

  114. Cohen RI, Marmur R, Norton WT, Mehler MF, Kessler JA (1996) Nerve growth factor and neurotrophin-3 differentially regulate the proliferation and survival of developing Rat brain oligodendrocytes. J Neurosci 16(20):6433–6442

    PubMed  CAS  Google Scholar 

  115. Dowling P, Ming X, Raval S, Husar W, Casaccia-Bonnefil P, Chao M et al (1999) Up-regulated p75NTR neurotrophin receptor on glial cells in MS plaques. Neurology 53(8):1676–1682

    Article  PubMed  CAS  Google Scholar 

  116. Copray JC, Kust BM, Mantingh-Otter I, Boddeke HW (2005) p75NTR independent oligodendrocyte death in cuprizone-induced demyelination in C57BL/6 mice. Neuropathol Appl Neurobiol 31(6):600–609

    Article  PubMed  CAS  Google Scholar 

  117. Wu J, Ohlsson M, Warner EA, Loo KK, Hoang TX, Voskuhl RR et al (2008) Glial reactions and degeneration of myelinated processes in spinal cord gray matter in chronic experimental autoimmune encephalomyelitis. Neuroscience 156(3):586–596

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  118. Beattie MS, Harrington AW, Lee R, Kim JY, Boyce SL, Longo FM et al (2002) ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36(3):375–386

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  119. Petratos S, Gonzales MF, Azari MF, Marriott M, Minichiello RA, Shipham KA et al (2004) Expression of the low-affinity neurotrophin receptor, p75(NTR), is upregulated by oligodendroglial progenitors adjacent to the subventricular zone in response to demyelination. Glia 48(1):64–75

    Article  PubMed  Google Scholar 

  120. Xiao J, Wong AW, Willingham MM, van den Buuse M, Kilpatrick TJ, Murray SS (2011) Brain-derived neurotrophic factor promotes central nervous system myelination via a direct effect upon oligodendrocytes. Neurosignals 18(3):186–202

    Article  CAS  Google Scholar 

  121. Xiao J, Ferner AH, Wong AW, Denham M, Kilpatrick TJ, Murray SS (2012) Extracellular signal-regulated kinase 1/2 signaling promotes oligodendrocyte myelination in vitro. J Neurochem 122(6):1167–1180

    Article  PubMed  CAS  Google Scholar 

  122. Wong AW, Xiao J, Kemper D, Kilpatrick TJ, Murray SS (2013) Oligodendroglial expression of TrkB independently regulates myelination and progenitor cell proliferation. J Neurosci Off J Soc Neurosci 33(11):4947–4957

    Article  CAS  Google Scholar 

  123. Vondran MW, Clinton-Luke P, Honeywell JZ, Dreyfus CF (2010) BDNF+/− mice exhibit deficits in oligodendrocyte lineage cells of the basal forebrain. Glia 58(7):848–856

    PubMed Central  PubMed  Google Scholar 

  124. Van’t Veer A, Du Y, Fischer TZ, Boetig DR, Wood MR, Dreyfus CF (2009) Brain-derived neurotrophic factor effects on oligodendrocyte progenitors of the basal forebrain are mediated through trkB and the MAP kinase pathway. J Neurosci Res 87(1):69–78

    Article  CAS  Google Scholar 

  125. VonDran MW, Singh H, Honeywell JZ, Dreyfus CF (2011) Levels of BDNF impact oligodendrocyte lineage cells following a cuprizone lesion. J Neurosci Offi J Soc Neurosci 31(40):14182–14190

    Article  CAS  Google Scholar 

  126. Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H (2002) BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 125(Pt 1):75–85

    Article  PubMed  Google Scholar 

  127. Zhu W, Acosta C, MacNeil BJ, Klonisch T, Cortes C, Doupe M, Gong Y, Namaka M (2014) Spinal cord brain derived neurotrophic factor (BDNF) responsive cells in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS): Implications in myelin repair. Res Immunol Int J (in press)

  128. De Santi L, Cantalupo L, Tassi M, Raspadori D, Cioni C, Annunziata P (2009) Higher expression of BDNF receptor gp145trkB is associated with lower apoptosis intensity in T cell lines in multiple sclerosis. J Neurol Sci 277(1–2):65–70

    Article  PubMed  CAS  Google Scholar 

  129. Bieber AJ, Kerr S, Rodriguez M (2003) Efficient central nervous system remyelination requires T cells. Ann Neurol 53(5):680–684

    Article  PubMed  Google Scholar 

  130. Shi D, Hirata H, Sasaki H, Morita A, Matsumoto M, Ohkaya S et al (1999) Expression of gp145trkB in the early stage of Schwann cell tube formation. J Orthop Sci Off J Jpn Orthop Assoc 4(1):22–27

    CAS  Google Scholar 

  131. Xiao J, Wong AW, Willingham MM, Kaasinen SK, Hendry IA, Howitt J et al (2009) BDNF exerts contrasting effects on peripheral myelination of NGF-dependent and BDNF-dependent DRG neurons. J Neurosci Off J Soc Neurosci 29(13):4016–4022

    Article  CAS  Google Scholar 

  132. Rawji KS, Yong VW (2013) The benefits and detriments of macrophages/microglia in models of multiple sclerosis. Clin Dev Immunol 2013:948976

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  133. Jurevics H, Largent C, Hostettler J, Sammond DW, Matsushima GK, Kleindienst A et al (2002) Alterations in metabolism and gene expression in brain regions during cuprizone-induced demyelination and remyelination. J Neurochem 82(1):126–136

    Article  PubMed  CAS  Google Scholar 

  134. Skripuletz T, Hackstette D, Bauer K, Gudi V, Pul R, Voss E et al (2013) Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain 136(Pt 1):147–167

    Article  PubMed  Google Scholar 

  135. Vaknin I, Kunis G, Miller O, Butovsky O, Bukshpan S, Beers DR et al (2011) Excess circulating alternatively activated myeloid (M2) cells accelerate ALS progression while inhibiting experimental autoimmune encephalomyelitis. PLoS One 6(11):e26921

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  136. Elkabes S, DiCicco-Bloom EM, Black IB (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci Off J Soc Neurosci 16(8):2508–2521

    CAS  Google Scholar 

  137. Zusso M, Methot L, Lo R, Greenhalgh AD, David S, Stifani S (2012) Regulation of postnatal forebrain amoeboid microglial cell proliferation and development by the transcription factor Runx1. J Neurosci Off J Soc Neurosci 32(33):11285–11298

    Article  CAS  Google Scholar 

  138. Liebl DJ, Huang W, Young W, Parada LF (2001) Regulation of Trk receptors following contusion of the rat spinal cord. Exp Neurol 167(1):15–26

    Article  PubMed  CAS  Google Scholar 

  139. Song XY, Li F, Zhang FH, Zhong JH, Zhou XF (2013) Peripherally-derived BDNF promotes regeneration of ascending sensory neurons after spinal cord injury. PLoS One 3(3):e1707

    Article  CAS  Google Scholar 

  140. Zhang X, Xu Y, Wang J, Zhou Q, Pu S, Jiang W et al (2012) The effect of intrathecal administration of glial activation inhibitors on dorsal horn BDNF overexpression and hind paw mechanical allodynia in spinal nerve ligated rats. J Neural Transm 119(3):329–336

    Article  PubMed  CAS  Google Scholar 

  141. Zhu ZW, Friess H, Wang L, Zimmermann A, Buchler MW (2001) Brain-derived neurotrophic factor (BDNF) is upregulated and associated with pain in chronic pancreatitis. Dig Dis Sci 46(8):1633–1639

    Article  PubMed  CAS  Google Scholar 

  142. Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T (2007) Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res 85(3):525–535

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  143. Lee DH, Geyer E, Flach AC, Jung K, Gold R, Flugel A et al (2012) Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination. Acta Neuropathol 123(2):247–258

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  144. Cellerino A, Carroll P, Thoenen H, Barde Y-A (1997) Reduced size of retinal ganglion cell axons and hypomyelination in mice lacking brain-derived neurotrophic factor. Mol Cell Neurosci 9(5–6):397–408

    Article  PubMed  CAS  Google Scholar 

  145. Djalali S, Holtje M, Grosse G, Rothe T, Stroh T, Grosse J et al (2005) Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development. J Neurochem 92(3):616–627

    Article  PubMed  CAS  Google Scholar 

  146. Du Y, Lercher LD, Zhou R, Dreyfus CF (2006) Mitogen-activated protein kinase pathway mediates effects of brain-derived neurotrophic factor on differentiation of basal forebrain oligodendrocytes. J Neurosci Res 84(8):1692–1702

    Article  PubMed  CAS  Google Scholar 

  147. Nakajima H, Uchida K, Yayama T, Kobayashi S, Guerrero AR, Furukawa S et al (2010) Targeted retrograde gene delivery of brain-derived neurotrophic factor suppresses apoptosis of neurons and oligodendroglia after spinal cord injury in rats. Spine 35(5):497–504

    Article  PubMed  Google Scholar 

  148. Linker RA, Lee DH, Demir S, Wiese S, Kruse N, Siglienti I et al (2010) Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis. Brain 133(Pt 8):2248–2263

    Article  PubMed  Google Scholar 

  149. Cao Q, Xu XM, Devries WH, Enzmann GU, Ping P, Tsoulfas P et al (2005) Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J Neurosci Off J Soc Neurosci 25(30):6947–6957

    Article  CAS  Google Scholar 

  150. Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE et al (1999) Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189(5):865–870

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  151. Skihar V, Silva C, Chojnacki A, Doring A, Stallcup WB, Weiss S et al (2009) Promoting oligodendrogenesis and myelin repair using the multiple sclerosis medication glatiramer acetate. Proc Natl Acad Sci U S A 106(42):17992–17997

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  152. Arnon R, Aharoni R (2009) Neuroprotection and neurogeneration in MS and its animal model EAE effected by glatiramer acetate. J Neural Transm 116(11):1443–1449

    Article  PubMed  CAS  Google Scholar 

  153. Lalive PH, Neuhaus O, Benkhoucha M, Burger D, Hohlfeld R, Zamvil SS et al (2011) Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs 25(5):401–414

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  154. Caggiula M, Batocchi AP, Frisullo G, Angelucci F, Patanella AK, Sancricca C et al (2006) Neurotrophic factors in relapsing remitting and secondary progressive multiple sclerosis patients during interferon beta therapy. Clin Immunol 118(1):77–82

    Article  PubMed  CAS  Google Scholar 

  155. Kala M, Miravalle A, Vollmer T (2011) Recent insights into the mechanism of action of glatiramer acetate. J Neuroimmunol 235(1–2):9–17

    Article  PubMed  CAS  Google Scholar 

  156. Bruck W, Wegner C (2011) Insight into the mechanism of laquinimod action. J Neurol Sci 306(1–2):173–179

    Article  PubMed  CAS  Google Scholar 

  157. Azoulay D, Vachapova V, Shihman B, Miler A, Karni A (2005) Lower brain-derived neurotrophic factor in serum of relapsing remitting MS: reversal by glatiramer acetate. J Neuroimmunol 167(1–2):215–218

    Article  PubMed  CAS  Google Scholar 

  158. La Mantia L, Munari LM, Lovati R (2010) Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev 5:CD004678

    PubMed  Google Scholar 

  159. Azoulay D, Urshansky N, Karni A (2008) Low and dysregulated BDNF secretion from immune cells of MS patients is related to reduced neuroprotection. J Neuroimmunol 195(1–2):186–193

    Article  PubMed  CAS  Google Scholar 

  160. De Santi L, Annunziata P, Sessa E, Bramanti P (2009) Brain-derived neurotrophic factor and TrkB receptor in experimental autoimmune encephalomyelitis and multiple sclerosis. J Neurol Sci 287(1–2):17–26

    Article  PubMed  CAS  Google Scholar 

  161. Makar TK, Bever CT, Singh IS, Royal W, Sahu SN, Sura TP (2009) Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle. J Neuroimmunol 210(1–2):40–51

    Article  PubMed  CAS  Google Scholar 

  162. McTigue DM, Horner PJ, Stokes BT, Gage FH (1998) Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult Rat spinal cord. J Neurosci 18(14):5354–5365

    PubMed  CAS  Google Scholar 

  163. Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H et al (2006) The effect of site and type of nerve injury on the expression of brain-derived neurotrophic factor in the dorsal root ganglion and on neuropathic pain behavior. Neuroscience 137(3):961–970

    Article  PubMed  CAS  Google Scholar 

  164. Ankeny DP, McTigue DM, Guan Z, Yan Q, Kinstler O, Stokes BT et al (2001) Pegylated brain-derived neurotrophic factor shows improved distribution into the spinal cord and stimulates locomotor activity and morphological changes after injury. Exp Neurol 170(1):85–100

    Article  PubMed  CAS  Google Scholar 

  165. Zvarova K, Murray E, Vizzard MA (2004) Changes in galanin immunoreactivity in rat lumbosacral spinal cord and dorsal root ganglia after spinal cord injury. J Comp Neurol 475(4):590–603

    Article  PubMed  CAS  Google Scholar 

  166. Vavrek R, Girgis J, Tetzlaff W, Hiebert GW, Fouad K (2006) BDNF promotes connections of corticospinal neurons onto spared descending interneurons in spinal cord injured rats. Brain 129(Pt 6):1534–1545

    Article  PubMed  CAS  Google Scholar 

  167. Gallo V, Armstrong RC (2008) Myelin repair strategies: a cellular view. Curr Opin Neurol 21(3):278–283

    Article  PubMed Central  PubMed  Google Scholar 

  168. Deogracias R, Yazdani M, Dekkers MP, Guy J, Ionescu MC, Vogt KE et al (2012) Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc Natl Acad Sci U S A 109(35):14230–14235

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  169. Ziemssen T, Kumpfel T, Klinkert WE, Neuhaus O, Hohlfeld R (2002) Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain 125(Pt 11):2381–2391

    Article  PubMed  Google Scholar 

  170. Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R (2005) The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc Natl Acad Sci U S A 102(52):19045–19050

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  171. Chen M, Valenzuela RM, Dhib-Jalbut S (2003) Glatiramer acetate-reactive T cells produce brain-derived neurotrophic factor. J Neurol Sci 215(1–2):37–44

    Article  PubMed  CAS  Google Scholar 

  172. Ben-Zeev B, Aharoni R, Nissenkorn A, Arnon R (2011) Glatiramer acetate (GA, Copolymer-1) an hypothetical treatment option for Rett syndrome. Med Hypotheses 76(2):190–193

    Article  PubMed  CAS  Google Scholar 

  173. Thone J, Ellrichmann G, Seubert S, Peruga I, Lee DH, Conrad R et al (2012) Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am J Path 180(1):267–274

    Article  PubMed  CAS  Google Scholar 

  174. Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A et al (2008) Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 371(9630):2085–2092

    Article  PubMed  CAS  Google Scholar 

  175. Ogier M, Wang H, Hong E, Wang Q, Greenberg ME, Katz DM (2007) Brain-derived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome. J Neurosci Off J Soc Neurosci 27(40):10912–10917

    Article  CAS  Google Scholar 

  176. Wang H, Chan SA, Ogier M, Hellard D, Wang Q, Smith C et al (2006) Dysregulation of brain-derived neurotrophic factor expression and neurosecretory function in Mecp2 null mice. J Neurosci Off J Soc Neurosci 26(42):10911–10915

    Article  CAS  Google Scholar 

  177. Fyffe SL, Neul JL, Samaco RC, Chao HT, Ben-Shachar S, Moretti P et al (2008) Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron 59(6):947–958

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  178. Deng V, Matagne V, Banine F, Frerking M, Ohliger P, Budden S et al (2007) FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice. Hum Mol Genet 16(6):640–650

    Article  PubMed  CAS  Google Scholar 

  179. Kline DD, Ogier M, Kunze DL, Katz DM (2010) Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in Mecp2-null mice. J Neurosci Off J Soc Neurosci 30(15):5303–5310

    Article  CAS  Google Scholar 

  180. Schmid DA, Yang T, Ogier M, Adams I, Mirakhur Y, Wang Q et al (2012) A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome. J Neurosci Off J Soc Neurosci 32(5):1803–1810

    Article  CAS  Google Scholar 

  181. Kron M, Lang M, Adams IT, Sceniak M, Longo F, Katz DM (2014) A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome. Dis Model Mech 7(9):1047–1055

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  182. Abuhatzira L, Makedonski K, Kaufman Y, Razin A, Shemer R (2007) MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production. Epigenetics 29:2(4)

    Google Scholar 

  183. Lu J, Kurejova M, Wirotanseng LN, Linker RA, Kuner R, Tappe-Theodor A (2012) Pain in experimental autoimmune encephalitis: a comparative study between different mouse models. J Neuroinflammation 9:233

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  184. Tegla CA, Azimzadeh P, Andrian-Albescu M, Martin A, Cudrici CD, Trippe R 3rd et al (2014) SIRT1 is decreased during relapses in patients with multiple sclerosis. Exp Mol Pathol 96(2):139–148

    Article  PubMed  CAS  Google Scholar 

  185. Zhang F, Shi Y, Wang L, Sriram S (2011) Role of HDAC3 on p53 expression and apoptosis in T cells of patients with multiple sclerosis. PLoS One 6(2):e16795

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  186. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC et al (2011) Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther J Am Soc Gene Ther 19(10):1769–1779

    Article  CAS  Google Scholar 

  187. Verbeek R, van Tol EA, van Noort JM (2005) Oral flavonoids delay recovery from experimental autoimmune encephalomyelitis in SJL mice. Biochem Pharmacol 70(2):220–228

    Article  PubMed  CAS  Google Scholar 

  188. Dasgupta S, Zhou Y, Jana M, Banik NL, Pahan K (2003) Sodium phenylacetate inhibits adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice at multiple steps. J Immunol 170(7):3874–3882

    Article  PubMed  CAS  Google Scholar 

  189. Yoshida M (2007) Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. Tanpakushitsu Kakusan Koso Protein Nucleic Acid Enzym 52(13 Suppl):1788–1789

    Google Scholar 

  190. Mason JL, Xuan S, Dragatsis I, Efstratiadis A, Goldman JE (2003) Insulin-like growth factor (IGF) signaling through type 1 IGF receptor plays an important role in remyelination. J Neurosci Off J Soc Neurosci 23(20):7710–7718

    CAS  Google Scholar 

  191. Dangond F, Gullans SR (1998) Differential expression of human histone deacetylase mRNAs in response to immune cell apoptosis induction by trichostatin A and butyrate. Biochem Biophys Res Commun 247(3):833–837

    Article  PubMed  CAS  Google Scholar 

  192. Liu LT, Chang HC, Chiang LC, Hung WC (2003) Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Res 63(12):3069–3072

    PubMed  CAS  Google Scholar 

  193. Rosenberg GA, Dencoff JE, Correa N Jr, Reiners M, Ford CC (1996) Effect of steroids on CSF matrix metalloproteinases in multiple sclerosis: relation to blood–brain barrier injury. Neurology 46(6):1626–1632

    Article  PubMed  CAS  Google Scholar 

  194. Piazza R, Magistroni V, Mogavero A, Andreoni F, Ambrogio C, Chiarle R et al (2013) Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex. Neoplasia 15(5):511–522

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  195. Gaub P, Tedeschi A, Puttagunta R, Nguyen T, Schmandke A, Di Giovanni S (2010) HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation. Cell Death Differ 17(9):1392–1408

    Article  PubMed  CAS  Google Scholar 

  196. Kim HJ, Chuang DM (2014) HDAC inhibitors mitigate ischemia-induced oligodendrocyte damage: potential roles of oligodendrogenesis, VEGF, and anti-inflammation. Am J Transl Res 6(3):206–223

    PubMed Central  PubMed  Google Scholar 

  197. Liu A, Han YR, Li J, Sun D, Ouyang M, Plummer MR et al (2007) The glial or neuronal fate choice of oligodendrocyte progenitors is modulated by their ability to acquire an epigenetic memory. J Neurosci Off J Soc Neurosci 27(27):7339–7343

    Article  CAS  Google Scholar 

  198. Lyssiotis CA, Walker J, Wu C, Kondo T, Schultz PG, Wu X (2007) Inhibition of histone deacetylase activity induces developmental plasticity in oligodendrocyte precursor cells. Proc Natl Acad Sci U S A 104(38):14982–14987

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  199. Shu L, Khor TO, Lee JH, Boyanapalli SS, Huang Y, Wu TY et al (2011) Epigenetic CpG demethylation of the promoter and reactivation of the expression of Neurog1 by curcumin in prostate LNCaP cells. AAPS J 13(4):606–614

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  200. Lupski GC Jr (2001) In: Valle DBA, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G (eds) Charcot-Marie-tooth peripheral neuropathies and related disorders. McGraw-Hill, New York

    Google Scholar 

  201. Khajavi M, Shiga K, Wiszniewski W, He F, Shaw CA, Yan J et al (2007) Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: a potential therapy for inherited neuropathy. Am J Hum Genet 81(3):438–453

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  202. Patzko A, Bai Y, Saporta MA, Katona I, Wu X, Vizzuso D et al (2012) Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice. Brain 135(Pt 12):3551–3566

    Article  PubMed Central  PubMed  Google Scholar 

  203. Kaushala P, Mehra RD, Dharc P (2014) Curcumin induced up-regulation of Myelin basic protein (MBP) ameliorates sodium arsenite induced neurotoxicity in developing rat cerebellum. J Anat Soc India 63(1):3–11

    Article  Google Scholar 

  204. Bohnen NI, Albin RL (2011) White matter lesions in Parkinson disease. Nat Rev Neurol 7(4):229–236

    Article  PubMed Central  PubMed  Google Scholar 

  205. Jansen JF, Vlooswijk MC, Majoie HM, de Krom MC, Aldenkamp AP, Hofman PA et al (2008) White matter lesions in patients with localization-related epilepsy. Investig Radiol 43(8):552–558

    Article  Google Scholar 

  206. Vaessen MJ, Jansen JF, Vlooswijk MC, Hofman PA, Majoie HJ, Aldenkamp AP et al (2012) White matter network abnormalities are associated with cognitive decline in chronic epilepsy. Cereb Cortex 22(9):2139–2147

    Article  PubMed  Google Scholar 

  207. Matsusue E, Sugihara S, Fujii S, Kinoshita T, Nakano T, Ohama E et al (2007) Cerebral cortical and white matter lesions in amyotrophic lateral sclerosis with dementia: correlation with MR and pathologic examinations. AJNR Am J Neuroradiol 28(8):1505–1510

    Article  PubMed  CAS  Google Scholar 

  208. Burns JM, Church JA, Johnson DK, Xiong C, Marcus D, Fotenos AF et al (2005) White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease. Arch Neurol 62(12):1870–1876

    Article  PubMed  Google Scholar 

  209. Kozlowski P, Raj D, Liu J, Lam C, Yung AC, Tetzlaff W (2008) Characterizing white matter damage in rat spinal cord with quantitative MRI and histology. J Neurotrauma 25(6):653–676

    Article  PubMed  Google Scholar 

  210. Tolwani RJ, Cosgaya JM, Varma S, Jacob R, Kuo LE, Shooter EM (2004) BDNF overexpression produces a long-term increase in myelin formation in the peripheral nervous system. J Neurosci Res 77(5):662–669

    Article  PubMed  CAS  Google Scholar 

  211. Du Y, Fischer TZ, Clinton-Luke P, Lercher LD, Dreyfus CF (2006) Distinct effects of p75 in mediating actions of neurotrophins on basal forebrain oligodendrocytes. Mol Cell Neurosci 31(2):366–375

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Special thanks to the Manitoba Multiple Sclerosis Research Network Organization (MMSRNO) for their continued support of advanced research in MS. The authors would also like to acknowledge the support from The Manitoba Medical Service Foundation Grant (MMSF) Canadian Paraplegic Association (CPA), University of Manitoba Research Grants Program (URGP), Bayshore Health Care Systems, College of Pharmacy at the University of Manitoba, and endMS for their continued support of research training and education in the field of MS.

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Authors and Affiliations

  1. College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E 0T5, Manitoba, Canada

    Tina KhorshidAhmad, Crystal Acosta, Claudia Cortes, Ted M. Lakowski, Surendiran Gangadaran & Michael Namaka

  2. Manitoba Multiple Sclerosis Research Network Organization (MMSRNO), Winnipeg, Canada

    Tina KhorshidAhmad, Crystal Acosta, Claudia Cortes, Ted M. Lakowski, Surendiran Gangadaran & Michael Namaka

  3. College of Medicine, University of Manitoba, Winnipeg, Canada

    Michael Namaka

  4. School of Medical Rehabilitation, College of Medicine, University of Manitoba, Winnipeg, Canada

    Michael Namaka

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  4. Ted M. Lakowski
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  5. Surendiran Gangadaran
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  6. Michael Namaka
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Correspondence to Michael Namaka.

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KhorshidAhmad, T., Acosta, C., Cortes, C. et al. Transcriptional Regulation of Brain-Derived Neurotrophic Factor (BDNF) by Methyl CpG Binding Protein 2 (MeCP2): a Novel Mechanism for Re-Myelination and/or Myelin Repair Involved in the Treatment of Multiple Sclerosis (MS). Mol Neurobiol 53, 1092–1107 (2016). https://doi.org/10.1007/s12035-014-9074-1

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  • DOI: https://doi.org/10.1007/s12035-014-9074-1

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