Remyelinating strategies in multiple sclerosis

Expert Review of Neurotherapeutics

Volumn 14, Issue 11, 2014, Pages 1315-1334

  Luessi, Felix ^a   Kuhlmann, Tanja ^b   Zipp, Frauke ^a  

^a Rhine Main Neuroscience Network   (Germany)

^b UNIVERSITY HOSPITAL MÜNSTER   (Germany)

Author keywords

drug target; multiple sclerosis; myelin repair; neurodegeneration; neuroprotection; oligodendrocytes; remyelination; treatment

Indexed keywords

BONE MORPHOGENETIC PROTEIN 4; CELL ADHESION MOLECULE; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 17; HYALURONIC ACID; IMMUNOGLOBULIN G; LEUCINE; NOTCH RECEPTOR; RETINOID X RECEPTOR GAMMA; SEMAPHORIN; UNCLASSIFIED DRUG; ZINC FINGER PROTEIN; IMMUNOSUPPRESSIVE AGENT;

CELL DIFFERENTIATION; CELLS; DEMYELINATION; GENE CONTROL; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MACROPHAGE; MICROGLIA; MULTIPLE SCLEROSIS; MYELINATION; NERVE FIBER DEGENERATION; NERVE INJURY; NONHUMAN; OLIGODENDROGLIA; PATHOGENESIS; REMYELINIZATION; REVIEW; STEM CELL; STEM CELL TRANSPLANTATION; WNT SIGNALING PATHWAY; DEMYELINATING DISEASES; DRUG EFFECTS; METABOLISM; MYELIN SHEATH; NERVE CELL; NERVE FIBER; PATHOLOGY;

AXONS; DEMYELINATING DISEASES; HUMANS; IMMUNOSUPPRESSIVE AGENTS; MULTIPLE SCLEROSIS; MYELIN SHEATH; NEURONS; OLIGODENDROGLIA;

EID: 84911941350     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/14737175.2014.969241     Document Type: Review

References (242)

1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343(13): 938-52
2. O'Connor P; Canadian Multiple Sclerosis Working Group. Key issues in the diagnosis and treatment of multiple sclerosis. An overview. Neurology 2002; 59(6 Suppl 3):S1-33
3. Luessi F, Siffrin V, Zipp F. Neurodegeneration in multiple sclerosis: novel treatment strategies. Expert Rev Neurother 2012;12(9):1061-76
4. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46(4):907-11
5. Beecham AH, Patsopoulos NA, Xifara DK, et al. International Multiple Sclerosis Genetics Consortium. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013;45(11):1353-60
6. Sawcer S, Hellenthal G, Pirinen M, et al. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium.Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476(7359):214-19
7. Kornek B, Storch MK, Weissert R, et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 2000;157(1):267-76
8. Pohl HB, Porcheri C, Mueggler T, et al. Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage. J Neurosci 2011;31(3):1069-80
9. Griffiths I, Klugmann M, Anderson T, et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 1998;280(5369):1610-13
10. Siffrin V, Vogt J, Radbruch H, et al. Multiple sclerosis-candidate mechanisms underlying CNS atrophy. Trends Neurosci 2010;33(4):202-10
11. Charcot J. Leçons sur les maladies du système nerveux faites à la Salpetrière. Adrien Delahaye, Bourneville, Paris: 1880
12. Kornek B, Lassmann H. Axonal pathology in multiple sclerosis. A historical note. Brain Pathol 1999;9(4):651-6
13. Inglese M, Ge Y, Filippi M, et al. Indirect evidence for early widespread gray matter involvement in relapsing-remitting multiple sclerosis. Neuroimage 2004;21(4):1825-9
14. Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120(Pt 3):393-9
15. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338(5): 278-85
16. Kuhlmann T, Lingfeld G, Bitsch A, et al. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002;125(Pt 10): 2202-12
17. Dutta R, McDonough J, Yin X, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 2006;59(3):478-89
18. Mahad DJ, Ziabreva I, Campbell G, et al. Mitochondrial changes within axons in multiple sclerosis. Brain 2009;132(Pt 5): 1161-74
19. Peterson JW, Bo L, Mork S, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001;50(3): 389-400
20. Vercellino M, Masera S, Lorenzatti M, et al. Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter. J Neuropathol Exp Neurol 2009;68(5):489-502
21. Wegner C, Esiri MM, Chance SA, et al. Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 2006;67(6): 960-7
22. Dutta R, Chang A, Doud MK, et al. Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann Neurol 2011;69(3):445-54
23. Dutta R, Trapp BD. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol 2011; 93(1):1-12
24. Mori F, Rossi S, Piccinin S, et al. Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis. J Neurosci 2013;33(49):19112-19
25. Dutta R, Chomyk AM, Chang A, et al. Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors. Ann Neurol 2013;73(5): 637-45
26. Imitola J, Chitnis T, Khoury SJ. Insights into the molecular pathogenesis of progression in multiple sclerosis: potential implications for future therapies. Arch Neurol 2006;63(1):25-33
27. Nishie M, Mori F, Ogawa M, et al. Multinucleated astrocytes in old demyelinated plaques in a patient with multiple sclerosis. Neuropathology 2004; 24(3):248-53
28. Clarke G, Collins RA, Leavitt BR, et al. A one-hit model of cell death in inherited neuronal degenerations. Nature 2000; 406(6792):195-9
29. Ge Y, Law M, Johnson G, et al. Preferential occult injury of corpus callosum in multiple sclerosis measured by diffusion tensor imaging. J Magn Reson Imaging 2004; 20(1):1-7
30. Baranzini SE, Srinivasan R, Khankhanian P, et al. Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis. Brain 2010;133(9): 2603-11
31. Baranzini SE, Wang J, Gibson RA, et al. Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet 2009; 18(4):767-78
32. Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009;5(5): 256-66
33. Barkhof F. MRI in multiple sclerosis: correlation with expanded disability status scale (EDSS). Mult Scler 1999;5(4):283-6
34. Zipp F. A new window in multiple sclerosis pathology: non-conventional quantitative magnetic resonance imaging outcomes. J Neurol Sci 2009;287(Suppl 1):S24-9
35. Lin X, Tench CR, Turner B, et al. Spinal cord atrophy and disability in multiple sclerosis over four years: application of a reproducible automated technique in monitoring disease progression in a cohort of the interferon beta-1a (Rebif) treatment trial. J Neurol Neurosurg Psychiatry 2003; 74(8):1090-4
36. Evangelou N, DeLuca GC, Owens T, Esiri MM. Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions. Brain 2005;128(Pt 1): 29-34
37. Arnold DL, Riess GT, Matthews PM, et al. Use of proton magnetic resonance spectroscopy for monitoring disease progression in multiple sclerosis. Ann Neurol 1994;36(1):76-82
38. De Stefano N, Matthews PM, Fu L, et al. Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 1998; 121(Pt 8):1469-77
39. Nave KA. Myelination and the trophic support of long axons. Nat Rev Neurosci 2010;11(4):275-83
40. Funfschilling U, Supplie LM, Mahad D, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 2012;485(7399):517-21
41. Kassmann CM, Lappe-Siefke C, Baes M, et al. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat Genet 2007;39(8): 969-76
42. Lappe-Siefke C, Goebbels S, Gravel M, et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet 2003;33(3): 366-74
43. Smith KJ, Blakemore WF, McDonald WI. Central remyelination restores secure conduction. Nature 1979;280(5721):395-6
44. Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 2009;8(3): 280-91
45. Bostock H, Sears TA. The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination. J Physiol 1978;280:273-301
46. Felts PA, Baker TA, Smith KJ. Conduction in segmentally demyelinated mammalian central axons. J Neurosci 1997;17(19): 7267-77
47. Su KG, Banker G, Bourdette D, Forte M. Axonal degeneration in multiple sclerosis: the mitochondrial hypothesis. Curr Neurol Neurosci Rep 2009;9(5):411-17
48. Mahad D, Ziabreva I, Lassmann H, Turnbull D. Mitochondrial defects in acute multiple sclerosis lesions. Brain 2008; 131(Pt 7):1722-35
49. Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47(6): 707-17
50. Lindquist S, Bodammer N, Kaufmann J, et al. Histopathology and serial, multimodal magnetic resonance imaging in a multiple sclerosis variant. Mult Scler 2007;13(4): 471-82
51. Zambonin JL, Zhao C, Ohno N, et al. Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Brain 2011;134(Pt 7): 1901-13
52. Jeffery ND, Blakemore WF. Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. Brain 1997;120(Pt 1):27-37
53. Irvine KA, Blakemore WF. Remyelination protects axons from demyelination-associated axon degeneration. Brain 2008;131(Pt 6):1464-77
54. Nave KA, Trapp BD. Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci 2008l;31:535-61
55. Manrique-Hoyos N, Jurgens T, Gronborg M, et al. Late motor decline after accomplished remyelination: impact for progressive multiple sclerosis. Ann Neurol 2012;71(2):227-44
56. Wilkins A, Chandran S, Compston A. A role for oligodendrocyte-derived IGF-1 in trophic support of cortical neurons. Glia 2001;36(1):48-57
57. Wilkins A, Majed H, Layfield R, et al. Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J Neurosci 2003;23(12):4967-74
58. Oluich LJ, Stratton JA, Xing YL, et al. Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination. J Neurosci 2012; 32(24):8317-30
59. Blakemore WF. Pattern of remyelination in the CNS. Nature 1974;249(457):577-8
60. Gledhill RF, Harrison BM, McDonald WI. Pattern of remyelination in the CNS. Nature 1973;244(5416):443-4
61. Bin JM, Rajasekharan S, Kuhlmann T, et al. Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration. Am J Pathol 2013;183(3):673-80
62. Chang A, Nishiyama A, Peterson J, et al. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci 2000;20(17): 6404-12
63. Gensert JM, Goldman JE. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron 1997;19(1): 197-203
64. Wolswijk G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 1998;18(2):601-9
65. Nishiyama A, Lin XH, Giese N, et al. Co-localization of NG2 proteoglycan and PDGF alpha-receptor on O2A progenitor cells in the developing rat brain. J Neurosci Res 1996;43(3):299-314
66. Pringle NP, Mudhar HS, Collarini EJ, Richardson WD. PDGF receptors in the rat CNS: during late neurogenesis, PDGF alpha-receptor expression appears to be restricted to glial cells of the oligodendrocyte lineage. Development 1992; 115(2):535-51
67. Rivers LE, Young KM, Rizzi M, et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 2008; 11(12):1392-401
68. Carroll WM, Jennings AR, Ironside LJ. Identification of the adult resting progenitor cell by autoradiographic tracking of oligodendrocyte precursors in experimental CNS demyelination. Brain 1998;121(Pt 2): 293-302
69. Groves AK, Barnett SC, Franklin RJ, et al. Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature 1993;362(6419):453-5
70. Nunes MC, Roy NS, Keyoung HM, et al. Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med 2003;9(4):439-47
71. Levine JM, Reynolds R. Activation and proliferation of endogenous oligodendrocyte precursor cells during ethidium bromide-induced demyelination. Exp Neurol 1999;160(2):333-47
72. Watanabe M, Toyama Y, Nishiyama A. Differentiation of proliferated NG2-positive glial progenitor cells in a remyelinating lesion. J Neurosci Res 2002;69(6):826-36
73. Fancy SP, Zhao C, Franklin RJ. Increased expression of Nkx2.2 and Olig2 identifies reactive oligodendrocyte progenitor cells responding to demyelination in the adult CNS. Mol Cell Neurosci 2004;27(3): 247-54
74. Siffrin V, Radbruch H, Glumm R, et al. In vivo imaging of partially reversible th17 cell-induced neuronal dysfunction in the course of encephalomyelitis. Immunity 2010;33(3):424-36
75. Fox RJ, Thompson A, Baker D, et al. Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS. Mult Scler 2012;18(11):1534-40
76. McTigue DM, Horner PJ, Stokes BT, Gage FH. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 1998;18(14):5354-65
77. Zhang Y, Argaw AT, Gurfein BT, et al. Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proc Natl Acad Sci USA 2009;106(45):19162-7
78. Keirstead HS, Blakemore WF. Identification of post-mitotic oligodendrocytes incapable of remyelination within the demyelinated adult spinal cord. J Neuropathol Exp Neurol 1997;56(11):1191-201
79. Mi S, Hu B, Hahm K, et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med 2007;13(10): 1228-33
80. Jeffery ND, Blakemore WF. Remyelination of mouse spinal cord axons demyelinated by local injection of lysolecithin. J Neurocytol 1995;24(10):775-81
81. Woodruff RH, Franklin RJ. Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti-galactocerebroside: a comparative study. Glia 1999;25(3): 216-28
82. Matsushima GK, Morell P. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 2001;11(1):107-16
83. Ludwin SK. Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab Invest 1978;39(6):597-612
84. Boretius S, Escher A, Dallenga T, et al. Assessment of lesion pathology in a new animal model of MS by multiparametric MRI and DTI. Neuroimage 2012;59(3): 2678-88
85. Rhodes KE, Raivich G, Fawcett JW. The injury response of oligodendrocyte precursor cells is induced by platelets, macrophages and inflammation-associated cytokines. Neuroscience 2006;140(1):87-100
86. Fancy SP, Baranzini SE, Zhao C, et al. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev 2009;23(13): 1571-85
87. Ye F, Chen Y, Hoang T, et al. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction. Nat Neurosci 2009;12(7):829-38
88. Stolt CC, Rehberg S, Ader M, et al. Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10. Genes Dev 2002;16(2):165-70
89. Nakatani H, Martin E, Hassani H, et al. Ascl1/Mash1 promotes brain oligodendrogenesis during myelination and remyelination. J Neurosci 2013;33(23): 9752-68
90. Arnett HA, Fancy SP, Alberta JA, et al. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science 2004;306(5704):2111-15
91. Wang Y, Imitola J, Rasmussen S, et al. Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis. Ann Neurol 2008;64(4):417-27
92. Nait-Oumesmar B, Picard-Riera N, Kerninon C, Baron-Van Evercooren A. The role of SVZ-derived neural precursors in demyelinating diseases: from animal models to multiple sclerosis. J Neurol Sci 2008; 265(1-2):26-31
93. Papadopoulou A, Menegola M, Kuhle J, et al. Lesion-to-ventricle distance and other risk factors for the persistence of newly formed black holes in relapsing-remitting multiple sclerosis. Mult Scler 2014;20(3): 322-30
94. Fancy SP, Harrington EP, Yuen TJ, et al. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nat Neurosci 2011;14(8):1009-16
95. Harroch S, Furtado GC, Brueck W, et al. A critical role for the protein tyrosine phosphatase receptor type Z in functional recovery from demyelinating lesions. Nat Genet 2002;32(3):411-14
96. Emery B. Regulation of oligodendrocyte differentiation and myelination. Science 2010;330(6005):779-82
97. Imitola J, Snyder EY, Khoury SJ. Genetic programs and responses of neural stem/progenitor cells during demyelination: potential insights into repair mechanisms in multiple sclerosis. Physiol Genomics 2003; 14(3):171-97
98. Duncan ID, Brower A, Kondo Y, et al. Extensive remyelination of the CNS leads to functional recovery. Proc Natl Acad Sci USA 2009;106(16):6832-6
99. Franklin RJ, ffrench-Constant C, Edgar JM, Smith KJ. Neuroprotection and repair in multiple sclerosis. Nat Rev Neurol 2012; 8(11):624-34
100. Patani R, Balaratnam M, Vora A, Reynolds R. Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathol Appl Neurobiol 2007; 33(3):277-87
101. Patrikios P, Stadelmann C, Kutzelnigg A, et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain 2006; 129(Pt 12):3165-72
102. Hagemeier K, Bruck W, Kuhlmann T. Multiple sclerosis-remyelination failure as a cause of disease progression. Histol Histopathol 2012;27(3):277-87
103. Raine CS, Scheinberg L, Waltz JM. Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion. Lab Invest 1981;45(6):534-46
104. Goldschmidt T, Antel J, Konig FB, et al. Remyelination capacity of the MS brain decreases with disease chronicity. Neurology 2009;72(22):1914-21
105. Albert M, Antel J, Bruck W, Stadelmann C. Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol 2007;17(2):129-38
106. Chang A, Staugaitis SM, Dutta R, et al. Cortical remyelination: a new target for repair therapies in multiple sclerosis. Ann Neurol 2012;72(6):918-26
107. Kuhlmann T, Miron V, Cui Q, et al. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 2008;131(Pt 7):1749-58
108. Boyd A, Zhang H, Williams A. Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models. Acta Neuropathol 2013; 125(6):841-59
109. Cui QL, Kuhlmann T, Miron VE, et al. Oligodendrocyte progenitor cell susceptibility to injury in multiple sclerosis. Am J Pathol 2013;183(2):516-25
110. Kieseier BC, Hartung HP. Interferon-beta and neuroprotection in multiple sclerosis-facts, hopes and phantasies. Exp Neurol 2007;203(1):1-4
111. Yong VW. Differential mechanisms of action of interferon-beta and glatiramer aetate in MS. Neurology 2002;59(6):802-8
112. Malik O, Compston DA, Scolding NJ. Interferon-beta inhibits mitogen induced astrocyte proliferation in vitro. J Neuroimmunol 1998;86(2):155-62
113. Sattler MB, Demmer I, Williams SK, et al. Effects of interferon-beta-1a on neuronal survival under autoimmune inflammatory conditions. Exp Neurol 2006;201(1):172-81
114. Bagnato F, Gupta S, Richert ND, et al. Effects of interferon beta-1b on black holes in multiple sclerosis over a 6-year period with monthly evaluations. Arch Neurol 2005;62(11):1684-8
115. Filippi M, Rovaris M, Inglese M, et al. Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet 2004; 364(9444):1489-96
116. Neuhaus O, Farina C, Yassouridis A, et al. Multiple sclerosis: comparison of copolymer-1-reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells. Proc Natl Acad Sci USA 2000; 97(13):7452-7
117. Aharoni R, Teitelbaum D, Sela M, Arnon R. Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 1997;94(20):10821-6
118. Arnon R, Aharoni R. Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci USA 2004;101(Suppl 2):14593-8
119. Ziemssen T, Kumpfel T, Klinkert WE, et al. Glatiramer acetate-specific T-helper 1-and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain 2002;125(Pt 11):2381-91
120. Filippi M, Rovaris M, Rocca MA, et al. Glatiramer acetate reduces the proportion of new MS lesions evolving into "black holes". Neurology 2001;57(4):731-3
121. Khan O, Shen Y, Bao F, et al. Long-term study of brain 1H-MRS study in multiple sclerosis: effect of glatiramer acetate therapy on axonal metabolic function and feasibility of long-Term H-MRS monitoring in multiple sclerosis. J Neuroimaging 2008; 18(3):314-19
122. Rosen H, Goetzl EJ. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 2005;5(7):560-70
123. Miron VE, Ludwin SK, Darlington PJ, et al. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am J Pathol 2010;176(6):2682-94
124. Jackson SJ, Giovannoni G, Baker D. Fingolimod modulates microglial activation to augment markers of remyelination. J Neuroinflammation 2011;8:76
125. Hu Y, Lee X, Ji B, et al. Sphingosine 1-phosphate receptor modulator fingolimod (FTY720) does not promote remyelination in vivo. Mol Cell Neurosci 2011;48(1): 72-81
126. Kim HJ, Miron VE, Dukala D, et al. Neurobiological effects of sphingosine 1-phosphate receptor modulation in the cuprizone model. Faseb J 2011;25(5): 1509-18
127. Al-Izki S, Pryce G, Jackson SJ, et al. Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Mult Scler 2011;17(8):939-48
128. Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362(5):387-401
129. Moreau T, Coles A, Wing M, et al. CAMPATH-IH in multiple sclerosis. Mult Scler 1996;1(6):357-65
130. Coles AJ, Compston DA, Selmaj KW, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008; 359(17):1786-801
131. Coles AJ. Alemtuzumab long-term safety and efficacy: five years of the CAMMS223 trial. Mult Scler 2010;16: S134-5
132. Jones JL, Anderson JM, Phuah CL, et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 2010;133(Pt 8): 2232-47
133. Zivadinov R, Dwyer MG, Hussein S, et al. Voxel-wise magnetization transfer imaging study of effects of natalizumab and IFNbeta-1a in multiple sclerosis. Mult Scler 2012;18(8):1125-34
134. Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 2009;284(20):13291-5
135. Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011; 134(Pt 3):678-92
136. Albrecht P, Bouchachia I, Goebels N, et al. Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation 2012;9:163
137. Moharregh-Khiabani D, Blank A, Skripuletz T, et al. Effects of fumaric acids on cuprizone induced central nervous system de-and remyelination in the mouse. PLoS One 2010;5(7):e11769
138. Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med 2012; 366(11):1000-9
139. Jolivel V, Luessi F, Masri J, et al. Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain 2013;136(Pt 4): 1048-66
140. Zou LP, Abbas N, Volkmann I, et al. Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue. Neuropharmacology 2002;42(5):731-9
141. Thöne J, Lee D, Seubert S, et al. Laquinimod ameliorates experimental autoimmune encephalomyelitis via BDNF-dependent mechanisms. Mult Scler 2010;16:S310
142. Bruck W, Pfortner R, Pham T, et al. Reduced astrocytic NF-kappaB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol 2012; 124(3):411-24
143. Fancy SP, Kotter MR, Harrington EP, et al. Overcoming remyelination failure in multiple sclerosis and other myelin disorders. Exp Neurol 2010;225(1):18-23
144. Chen Y, Wu H, Wang S, et al. The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nat Neurosci 2009;12(11): 1398-406
145. Emery B, Agalliu D, Cahoy JD, et al. Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell 2009;138(1):172-85
146. Koenning M, Jackson S, Hay CM, et al. Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS. J Neurosci 2012;32(36):12528-42
147. Howng SY, Avila RL, Emery B, et al. ZFP191 is required by oligodendrocytes for CNS myelination. Genes Dev 2010;24(3): 301-11
148. Huang JK, Jarjour AA, Nait Oumesmar B, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci 2011;14(1):45-53
149. Altucci L, Leibowitz MD, Ogilvie KM, et al. RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov 2007;6(10):793-810
150. Ballanger F, Nguyen JM, Khammari A, Dreno B. Evolution of clinical and molecular responses to bexarotene treatment in cutaneous T-cell lymphoma. Dermatology 2010;220(4):370-5
151. Cramer PE, Cirrito JR, Wesson DW, et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 2012;335(6075): 1503-6
152. Kotter MR, Li WW, Zhao C, Franklin RJ. Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 2006;26(1): 328-32
153. Xin M, Yue T, Ma Z, et al. Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1-null mice. J Neurosci 2005;25(6):1354-65
154. Lecca D, Trincavelli ML, Gelosa P, et al. The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. PLoS One 2008;3(10):e3579
155. Fumagalli M, Daniele S, Lecca D, et al. Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation. J Biol Chem 2011;286(12):10593-604
156. Ceruti S, Vigano F, Boda E, et al. Expression of the new P2Y-like receptor GPR17 during oligodendrocyte precursor cell maturation regulates sensitivity to ATP-induced death. Glia 2011;59(3): 363-78
157. Genoud S, Lappe-Siefke C, Goebbels S, et al. Notch1 control of oligodendrocyte differentiation in the spinal cord. J Cell Biol 2002;158(4):709-18
158. John GR, Shankar SL, Shafit-Zagardo B, et al. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med 2002; 8(10):1115-21
159. Stidworthy MF, Genoud S, Li WW, et al. Notch1 and Jagged1 are expressed after CNS demyelination, but are not a major rate-determining factor during remyelination. Brain 2004;127(Pt 9): 1928-41
160. Seifert T, Bauer J, Weissert R, et al. Notch1 and its ligand Jagged1 are present in remyelination in a T-cell-and antibody-mediated model of inflammatory demyelination. Acta Neuropathol 2007; 113(2):195-203
161. Jurynczyk M, Jurewicz A, Bielecki B, et al. Inhibition of Notch signaling enhances tissue repair in an animal model of multiple sclerosis. J Neuroimmunol 2005;170(1-2): 3-10
162. Hoyne GF, Dallman MJ, Champion BR, Lamb JR. Notch signalling in the regulation of peripheral immunity. Immunol Rev 2001;182:215-27
163. Wang S, Sdrulla AD, diSibio G, et al. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 1998;21(1):63-75
164. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004;303(5663):1483-7
165. Edwards JP, Zhang X, Frauwirth KA, Mosser DM. Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 2006;80(6):1298-307
166. Cash E, Zhang Y, Rott O. Microglia present myelin antigens to T cells after phagocytosis of oligodendrocytes. Cell Immunol 1993;147(1):129-38
167. Banati RB, Gehrmann J, Schubert P, Kreutzberg GW. Cytotoxicity of microglia. Glia 1993;7(1):111-18
168. Kotter MR, Zhao C, van Rooijen N, Franklin RJ. Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis 2005;18(1):166-75
169. Ruckh JM, Zhao JW, Shadrach JL, et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 2012;10(1):96-103
170. Miron VE, Boyd A, Zhao JW, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 2013;16(9): 1211-18
171. Kondo T, Raff MC. A role for Noggin in the development of oligodendrocyte precursor cells. Dev Biol 2004;267(1): 242-51
172. Grinspan JB, Edell E, Carpio DF, et al. Stage-specific effects of bone morphogenetic proteins on the oligodendrocyte lineage. J Neurobiol 2000;43(1):1-17
173. Gross RE, Mehler MF, Mabie PC, et al. Bone morphogenetic proteins promote astroglial lineage commitment by mammalian subventricular zone progenitor cells. Neuron 1996;17(4):595-606
174. Sabo JK, Aumann TD, Merlo D, et al. Remyelination is altered by bone morphogenic protein signaling in demyelinated lesions. J Neurosci 2011; 31(12):4504-10
175. Deininger M, Meyermann R, Schluesener H . Detection of two transforming growth factor-beta-related morphogens, bone morphogenetic proteins-4 and-5, in RNA of multiple sclerosis and Creutzfeldt-Jakob disease lesions. Acta Neuropathol 1995;90(1):76-9
176. Mi S, Miller RH, Lee X, et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci 2005; 8(6):745-51
177. Mi S, Miller RH, Tang W, et al. Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells. Ann Neurol 2009;65(3):304-15
178. Rudick RA, Mi S, Sandrock AW Jr. LINGO-1 antagonists as therapy for multiple sclerosis: in vitro and in vivo evidence. Expert Opin Biol Ther 2008; 8(10):1561-70
179. Piaton G, Aigrot MS, Williams A, et al. Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system. Brain 2011;134(Pt 4):1156-67
180. Williams A, Piaton G, Aigrot MS, et al. Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis Brain 2007;130(Pt 10):2554-65
181. Syed YA, Hand E, Mobius W, et al. Inhibition of CNS remyelination by the presence of semaphorin 3A. J Neurosci 2011;31(10):3719-28
182. Back SA, Tuohy TM, Chen H, et al. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med 2005; 11(9):966-72
183. Struve J, Maher PC, Li YQ, et al. Disruption of the hyaluronan-based extracellular matrix in spinal cord promotes astrocyte proliferation. Glia 2005;52(1): 16-24
184. Preston M, Gong X, Su W, et al. Digestion products of the PH20 hyaluronidase inhibit remyelination. Ann Neurol 2013;73(2): 266-80
185. Sloane JA, Batt C, Ma Y, et al. Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2. Proc Natl Acad Sci USA 2010; 107(25):11555-60
186. Maness PF, Schachner M. Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat Neurosci 2007;10(1):19-26
187. Ronn LC, Hartz BP, Bock E. The neural cell adhesion molecule (NCAM) in development and plasticity of the nervous system. Exp Gerontol 1998;33(7-8):853-64
188. Charles P, Reynolds R, Seilhean D, et al. Re-expression of PSA-NCAM by demyelinated axons: an inhibitor of remyelination in multiple sclerosis Brain 2002;125(Pt 9):1972-9
189. Seki T, Arai Y. Distribution and possible roles of the highly polysialylated neural cell adhesion molecule (NCAM-H) in the developing and adult central nervous system. Neurosci Res 1993;17(4):265-90
190. Trotter J, Bitter-Suermann D, Schachner M. Differentiation-regulated loss of the polysialylated embryonic form and expression of the different polypeptides of the neural cell adhesion molecule by cultured oligodendrocytes and myelin. J Neurosci Res 1989;22(4):369-83
191. Laursen LS, Chan CW, ffrench-Constant C. An integrin-contactin complex regulates CNS myelination by differential Fyn phosphorylation. J Neurosci 2009;29(29): 9174-85
192. White R, Gonsior C, Kramer-Albers EM, et al. Activation of oligodendroglial Fyn kinase enhances translation of mRNAs transported in hnRNP A2-dependent RNA granules. J Cell Biol 2008;181(4): 579-86
193. Barbin G, Aigrot MS, Charles P, et al. Axonal cell-adhesion molecule L1 in CNS myelination. Neuron Glia Biol 2004;1(1): 65-72
194. Kubasak MD, Hedlund E, Roy RR, et al. L1 CAM expression is increased surrounding the lesion site in rats with complete spinal cord transection as neonates. Exp Neurol 2005;194(2):363-75
195. Roonprapunt C, Huang W, Grill R, et al. Soluble cell adhesion molecule L1-Fc promotes locomotor recovery in rats after spinal cord injury. J Neurotrauma 2003; 20(9):871-82
196. Xu G, Nie DY, Wang WZ, et al. Optic nerve regeneration in polyglycolic acid-chitosan conduits coated with recombinant L1-Fc. Neuroreport 2004; 15(14):2167-72
197. Zhang Y, Bo X, Schoepfer R, et al. Growth-associated protein GAP-43 and L1 act synergistically to promote regenerative growth of Purkinje cell axons in vivo. Proc Natl Acad Sci USA 2005; 102(41):14883-8
198. Bernard F, Moreau-Fauvarque C, Heitz-Marchaland C, et al. Role of transmembrane semaphorin Sema6A in oligodendrocyte differentiation and myelination. Glia 2012;60(10):1590-604
199. Fancy SP, Glasgow SM, Finley M, et al. Evidence that nuclear factor IA inhibits repair after white matter injury. Ann Neurol 2012;72(2):224-33
200. Kuboyama K, Fujikawa A, Masumura M, et al. Protein tyrosine phosphatase receptor type z negatively regulates oligodendrocyte differentiation and myelination. PLoS One 2012;7(11):e48797
201. Schmidt F, van den Eijnden M, Pescini Gobert R, et al. Identification of VHY/Dusp15 as a regulator of oligodendrocyte differentiation through a systematic genomics approach. PLoS One 2012;7(7):e40457
202. Deshmukh VA, Tardif V, Lyssiotis CA, et al. A regenerative approach to the treatment of multiple sclerosis. Nature 2013;502(7471):327-32
203. Buckley CE, Goldsmith P, Franklin RJ. Zebrafish myelination: a transparent model for remyelination Dis Model Mech 2008; 1(4-5):221-8
204. Sun Y, Xu CC, Li J, et al. Transplantation of oligodendrocyte precursor cells improves locomotion deficits in rats with spinal cord irradiation injury. PLoS One 2013;8(2): e57534
205. Wu B, Sun L, Li P, et al. Transplantation of oligodendrocyte precursor cells improves myelination and promotes functional recovery after spinal cord injury. Injury 2012;43(6):794-801
206. Uchida N, Chen K, Dohse M, et al. Human neural stem cells induce functional myelination in mice with severe dysmyelination. Sci Transl Med 2012; 4(155):155-136
207. Lindvall O, Kokaia Z. Stem cells in human neurodegenerative disorders-time for clinical translation J Clin Invest 2010;120(1):29-40
208. Blakemore WF, Chari DM, Gilson JM, Crang AJ. Modelling large areas of demyelination in the rat reveals the potential and possible limitations of transplanted glial cells for remyelination in the CNS. Glia 2002;38(2):155-68
209. Wang S, Bates J, Li X, et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 2013;12(2):252-64
210. Sim FJ, Zhao C, Penderis J, Franklin RJ. The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J Neurosci 2002;22(7):2451-9
211. Hinks GL, Franklin RJ. Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats. Mol Cell Neurosci 2000;16(5):542-56
212. Shen S, Sandoval J, Swiss VA, et al. Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci 2008;11(9):1024-34
213. Tang DG, Tokumoto YM, Raff MC. Long-term culture of purified postnatal oligodendrocyte precursor cells. Evidence for an intrinsic maturation program that plays out over months. J Cell Biol 2000;148(5): 971-84
214. Jaskelioff M, Muller FL, Paik JH, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 2011;469(7328):102-6
215. Shields SA, Gilson JM, Blakemore WF, Franklin RJ. Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination. Glia 1999;28(1):77-83
216. Lucchinetti CF, Popescu BF, Bunyan RF, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011;365(23):2188-97
217. Howell OW, Reeves CA, Nicholas R, et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011;134(Pt 9):2755-71
218. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol 2012;30: 429-57
219. Brown RA, Narayanan S, Arnold DL. Segmentation of magnetization transfer ratio lesions for longitudinal analysis of demyelination and remyelination in multiple sclerosis. Neuroimage 2012;66c: 103-9
220. Fox RJ, Cronin T, Lin J, et al. Measuring myelin repair and axonal loss with diffusion tensor imaging. AJNR Am J Neuroradiol 2011;32(1):85-91
221. Sinnecker T, Mittelstaedt P, Dorr J, et al. Multiple sclerosis lesions and irreversible brain tissue damage: a comparative ultrahigh-field strength magnetic resonance imaging study. Arch Neurol 2012;69(6): 739-45
222. Stankoff B, Freeman L, Aigrot MS, et al. Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-(1)(1)C]-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole. Ann Neurol 2011; 69(4):673-80
223. Fisher E, Rudick RA, Simon JH, et al. Eight-year follow-up study of brain atrophy in patients with MS. Neurology 2002;59(9): 1412-20
224. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 2006;113(2):324-32
225. Henderson AP, Trip SA, Schlottmann PG, et al. An investigation of the retinal nerve fibre layer in progressive multiple sclerosis using optical coherence tomography. Brain 2008;131(Pt 1):277-87
226. Leocani L, Rovaris M, Boneschi FM, et al. Multimodal evoked potentials to assess the evolution of multiple sclerosis: a longitudinal study. J Neurol Neurosurg Psychiatry 2006;77(9):1030-5
227. Jacobs L, Rudick R, Simon J. Extended observations on MS patients treated with IM interferon-beta1a (Avonex): implications for modern MS trials and therapeutics. J Neuroimmunol 2000;107(2):167-73
228. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996;39(3):285-94
229. Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007;370(9585):389-97
230. Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001; 49(3):290-7
231. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45(7): 1268-76
232. Edan G, Comi G, Le Page E, et al. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry 2011;82(12):1344-50
233. Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360(9350):2018-25
234. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354(9): 899-910
235. Confavreux C, O'Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13(3):247-56
236. O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365(14):1293-303
237. O'Connor PW, Li D, Freedman MS, et al. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 2006;66(6):894-900
238. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012; 78(14):1069-78
239. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380(9856): 1829-39
240. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367(12):1087-97
241. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367(12):1098-107
242. Kappos L, Gold R, Miller DH, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008;372(9648):1463-72