Neurodegeneration in multiple sclerosis: Novel treatment strategies

Expert Review of Neurotherapeutics

Volumn 12, Issue 9, 2012, Pages 1061-1077

  Luessi, Felix ^a   Siffrin, Volker ^a   Zipp, Frauke ^a  

^a UNIVERSITY MEDICAL CENTER MAINZ   (Germany)

Author keywords

multiple sclerosis; neurodegeneration; neuronal injury; neuroprotection; treatment

Indexed keywords

ALEMTUZUMAB; AMILORIDE; BETA1A INTERFERON; BG 00012; CANNABIS; DACLIZUMAB; EPIGALLOCATECHIN GALLATE; FINGOLIMOD; FLUPIRTINE; FUMARIC ACID; GLATIRAMER; INTERFERON BETA SERINE; LAMOTRIGINE; LAQUINIMOD; MITOXANTRONE; NATALIZUMAB; PLACEBO; RECOMBINANT ERYTHROPOIETIN; RILUZOLE; RITUXIMAB; SIMVASTATIN; TERIFLUNOMIDE; TETRAHYDROCANNABINOLIC ACID; UNCLASSIFIED DRUG;

ALLERGIC ENCEPHALOMYELITIS; AUTOIMMUNE DISEASE; AXONAL INJURY; BRAIN ATROPHY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; DISEASE COURSE; EXPANDED DISABILITY STATUS SCALE; HUMAN; IDIOPATHIC THROMBOCYTOPENIC PURPURA; MULTIPLE SCLEROSIS; NATURAL KILLER CELL; NERVE DEGENERATION; NERVE FIBER DEGENERATION; NEUROPROTECTION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OPTICAL COHERENCE TOMOGRAPHY; REVIEW; THYROID DISEASE; VISUAL ACUITY;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; EDUCATION, MEDICAL, CONTINUING; EVIDENCE-BASED MEDICINE; HUMANS; MOLECULAR TARGETED THERAPY; MULTIPLE SCLEROSIS; NEURODEGENERATIVE DISEASES; NEURONS; NEUROPROTECTIVE AGENTS;

EID: 84867290307     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.12.59     Document Type: Review

References (161)

1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N. Engl. J. Med. 343(13), 938-952 (2000).
2. O'Connor P; Canadian Multiple Sclerosis Working Group. Key issues in the diagnosis and treatment of multiple sclerosis. An overview. Neurology 59(6 Suppl. 3), S1-33 (2002).
3. 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 46(4), 907-911 (1996).
4. Siffrin V, Vogt J, Radbruch H, Nitsch R, Zipp F. Multiple sclerosis-candidate mechanisms underlying CNS atrophy. Trends Neurosci. 33(4), 202-210 (2010).
5. Charcot JM. [Clinical Lectures on the Diseases of the Nervous System from Salpetrière Hospital (4th Edition).] New Sydenham Society, Bourneville, Paris (1880).
6. Kornek B, Lassmann H. Axonal pathology in multiple sclerosis. A historical note. Brain Pathol. 9(4), 651-656 (1999).
7. Inglese M, Ge Y, Filippi M, Falini A, Grossman RI, Gonen O. Indirect evidence for early widespread gray matter involvement in relapsing-remitting multiple sclerosis. Neuroimage 21(4), 1825-1829 (2004).
8. Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 120(Pt 3), 393-399 (1997).
9. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338(5), 278-285 (1998).
10. Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Brück W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125(Pt 10), 2202-2212 (2002).
11. Boø L, Vedeler CA, Nyland H, Trapp BD, Moørk SJ. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult. Scler. 9(4), 323-331 (2003).
12. Kutzelnigg A, Lucchinetti CF, Stadelmann C et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128(Pt 11), 2705-2712 (2005).
13. Bjartmar C, Kinkel RP, Kidd G, Rudick RA, Trapp BD. Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 57(7), 1248-1252 (2001).
14. De Stefano N, Narayanan S, Francis GS et al. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch. Neurol. 58(1), 65-70 (2001).
15. Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat. Rev. Neurol. 5(5), 256-266 (2009).
16. Barkhof F. MRI in multiple sclerosis: correlation with expanded disability status scale (EDSS). Mult. Scler. 5(4), 283-286 (1999).
17. Zipp F. A new window in multiple sclerosis pathology: non-conventional quantitative magnetic resonance imaging outcomes. J. Neurol. Sci. 287(Suppl. 1), S24-S29 (2009).
18. Bock M, Brandt AU, Dörr J et al. Time domain and spectral domain optical coherence tomography in multiple sclerosis: a comparative cross-sectional study. Mult. Scler. 16(7), 893-896 (2010).
19. Zivadinov R, Reder AT, Filippi M et al. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology 71(2), 136-144 (2008).
20. Simon JH. Brain atrophy in multiple sclerosis: what we know and would like to know. Mult. Scler. 12(6), 679-687 (2006).
21. Smith SM, De Stefano N, Jenkinson M, Matthews PM. Normalized accurate measurement of longitudinal brain change. J. Comput. Assist. Tomogr. 25(3), 466-475 (2001).
22. Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L. Use of the brain parenchymal fraction to measure whole-brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 53(8), 1698-1704 (1999).
23. Fisher E, Rudick RA, Simon JH et al. Eight-year follow-up study of brain atrophy in patients with MS. Neurology 59(9), 1412-1420 (2002).
24. Zivadinov R, Stosic M, Cox JL, Ramasamy DP, Dwyer MG. The place of conventional MRI and newly emerging MRI techniques in monitoring different aspects of treatment outcome. J. Neurol. 255(Suppl. 1), 61-74 (2008).
25. van Walderveen MA, Kamphorst W, Scheltens P et al. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 50(5), 1282-1288 (1998).
26. van Waesberghe JH, Kamphorst W, De Groot CJ et al. Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann. Neurol. 46(5), 747-754 (1999).
27. Giacomini PS, Arnold DL. Nonconventional MRI techniques for measuring neuroprotection, repair and plasticity in multiple sclerosis. Curr. Opin. Neurol. 21(3), 272-277 (2008).
28. De Stefano N, Filippi M. MR spectroscopy in multiple sclerosis. J. Neuroimaging 17(Suppl. 1), 31S-35S (2007).
29. Bjartmar C, Kidd G, Mörk S, Rudick R, Trapp BD. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann. Neurol. 48(6), 893-901 (2000).
30. 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 121(Pt 8), 1469-1477 (1998).
31. van Walderveen MA, Barkhof F, Pouwels PJ, van Schijndel RA, Polman CH, Castelijns JA. Neuronal damage in T1-hypointense multiple sclerosis lesions demonstrated in vivo using proton magnetic resonance spectroscopy. Ann. Neurol. 46(1), 79-87 (1999).
32. Filippi M, Rocca MA. Magnetization transfer magnetic resonance imaging in the assessment of neurological diseases. J. Neuroimaging 14(4), 303-313 (2004).
33. Agosta F, Rovaris M, Pagani E et al. Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis. Ann. Neurol. 46, 747-754 (1999).
34. Schmierer K, Scaravilli F, Altmann DR, Barker GJ, Miller DH. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann. Neurol. 56(3), 407-415 (2004).
35. Trip SA, Schlottmann PG, Jones SJ et al. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann. Neurol. 58(3), 383-391 (2005).
36. Fisher JB, Jacobs DA, Markowitz CE et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 113(2), 324-332 (2006).
37. Pulicken M, Gordon-Lipkin E, Balcer LJ, Frohman E, Cutter G, Calabresi PA. Optical coherence tomography and disease subtype in multiple sclerosis. Neurology 69(22), 2085-2092 (2007).
38. Gordon-Lipkin E, Chodkowski B, Reich DS et al. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology 69(16), 1603-1609 (2007).
39. Serbecic N, Aboul-Enein F, Beutelspacher SC et al. High resolution spectral domain optical coherence tomography (SD-OCT) in multiple sclerosis: the first follow-up study over two years. PLoS ONE 6(5), e19843 (2011).
40. Sawcer S, Hellenthal G, Pirinen M et al.; International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359), 214-219 (2011).
41. Traugott U, Reinherz EL, Raine CS. Multiple sclerosis. Distribution of T cells, T cell subsets and Ia-positive macrophages in lesions of different ages. J. Neuroimmunol. 4(3), 201-221 (1983).
42. Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Brück W. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123(Pt 6), 1174-1183 (2000).
43. Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 8(3), 280-291 (2009).
44. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726), 1314-1318 (2005).
45. Remington LT, Babcock AA, Zehntner SP, Owens T. Microglial recruitment, activation, and proliferation in response to primary demyelination. Am. J. Pathol. 170(5), 1713-1724 (2007).
46. Trapp BD, Wujek JR, Criste GA et al. Evidence for synaptic stripping by cortical microglia. Glia 55(4), 360-368 (2007).
47. Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119-145 (2009).
48. Vogt J, Paul F, Aktas O et al. Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis. Ann. Neurol. 66(3), 310-322 (2009).
49. Hohlfeld R. Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain 120(Pt 5), 865-916 (1997).
50. Heppner FL, Greter M, Marino D et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat. Med. 11(2), 146-152 (2005).
51. Babbe H, Roers A, Waisman A et al. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J. Exp. Med. 192(3), 393-404 (2000).
52. Jacobsen M, Cepok S, Quak E et al. Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients. Brain 125(Pt 3), 538-550 (2002).
53. Hu D, Ikizawa K, Lu L, Sanchirico ME, Shinohara ML, Cantor H. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat. Immunol. 5(5), 516-523 (2004).
54. Lu L, Ikizawa K, Hu D, Werneck MB, Wucherpfennig KW, Cantor H. Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A inhibitory pathway. Immunity 26(5), 593-604 (2007).
55. Jiang H, Curran S, Ruiz-Vazquez E, Liang B, Winchester R, Chess L. Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor V ? repertoire during experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 100(14), 8378-8383 (2003).
56. Meuth SG, Herrmann AM, Simon OJ et al. Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death. J. Neurosci. 29(49), 15397-15409 (2009).
57. Medana IM, Gallimore A, Oxenius A, Martinic MM, Wekerle H, Neumann H. MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur. J. Immunol. 30(12), 3623-3633 (2000).
58. Medana I, Martinic MA, Wekerle H, Neumann H. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am. J. Pathol. 159(3), 809-815 (2001).
59. Linker RA, Sendtner M, Gold R. Mechanisms of axonal degeneration in EAE-lessons from CNTF and MHC I knockout mice. J. Neurol. Sci. 233(1-2), 167-172 (2005).
60. Koh DR, Fung-Leung WP, Ho A, Gray D, Acha-Orbea H, Mak TW. Less mortality but more relapses in experimental allergic encephalomyelitis in CD8?/? mice. Science 256(5060), 1210-1213 (1992).
61. Sun D, Qin Y, Chluba J, Epplen JT, Wekerle H. Suppression of experimentally induced autoimmune encephalomyelitis by cytolytic T-T cell interactions. Nature 332(6167), 843-845 (1988).
62. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH; Ustekinumab MS Investigators. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a Phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 7(9), 796-804 (2008).
63. Oksenberg JR, Barcellos LF, Cree BA et al. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am. J. Hum. Genet. 74(1), 160-167 (2004).
64. Mangalam A, Luckey D, Basal E et al. HLA-DQ8 (DQB1*0302)-restricted Th17 cells exacerbate experimental autoimmune encephalomyelitis in HLA-DR3-transgenic mice. J. Immunol. 182(8), 5131-5139 (2009).
65. Nitsch R, Pohl EE, Smorodchenko A, Infante-Duarte C, Aktas O, Zipp F. Direct impact of T cells on neurons revealed by two-photon microscopy in living brain tissue. J. Neurosci. 24(10), 2458-2464 (2004).
66. Aktas O, Smorodchenko A, Brocke S et al. Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 46(3), 421-432 (2005).
67. Nitsch R, Bechmann I, Deisz RA et al. Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 356(9232), 827-828 (2000).
68. 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 33(3), 424-436 (2010).
69. Arnold DL, Riess GT, Matthews PM et al. Use of proton magnetic resonance spectroscopy for monitoring disease progression in multiple sclerosis. Ann. Neurol. 36(1), 76-82 (1994).
70. Bostock H, Sears TA. The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination. J. Physiol. (Lond.) 280, 273-301 (1978).
71. Felts PA, Baker TA, Smith KJ. Conduction in segmentally demyelinated mammalian central axons. J. Neurosci. 17(19), 7267-7277 (1997).
72. Dutta R, McDonough J, Yin X et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann. Neurol. 59(3), 478-489 (2006).
73. Su KG, Banker G, Bourdette D, Forte M. Axonal degeneration in multiple sclerosis: the mitochondrial hypothesis. Curr. Neurol. Neurosci. Rep. 9(5), 411-417 (2009).
74. Mahad D, Ziabreva I, Lassmann H, Turnbull D. Mitochondrial defects in acute multiple sclerosis lesions. Brain 131(Pt 7), 1722-1735 (2008).
75. Mahad DJ, Ziabreva I, Campbell G et al. Mitochondrial changes within axons in multiple sclerosis. Brain 132(Pt 5), 1161-1174 (2009).
76. Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47(6), 707-717 (2000).
77. Lindquist S, Bodammer N, Kaufmann J et al. Histopathology and serial, multimodal magnetic resonance imaging in a multiple sclerosis variant. Mult. Scler. 13(4), 471-482 (2007).
78. Yang XO, Nurieva R, Martinez GJ et al. Molecular antagonism and plasticity of regulatory and inflammatory T-cell programs. Immunity 29(1), 44-56 (2008).
79. Nikolaeva MA, Mukherjee B, Stys PK. Na+-dependent sources of intra-axonal Ca2+ release in rat optic nerve during in vitro chemical ischemia. J. Neurosci. 25(43), 9960-9967 (2005).
80. Stys PK, Waxman SG, Ransom BR. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger. J. Neurosci. 12(2), 430-439 (1992).
81. Stys PK, Ransom BR, Waxman SG, Davis PK. Role of extracellular calcium in anoxic injury of mammalian central white matter. Proc. Natl Acad. Sci. USA 87(11), 4212-4216 (1990).
82. Stys PK, Jiang Q. Calpain-dependent neurofilament breakdown in anoxic and ischemic rat central axons. Neurosci. Lett. 328(2), 150-154 (2002).
83. Nave KA, Trapp BD. Axon-glial signaling and the glial support of axon function. Annu. Rev. Neurosci. 31, 535-561 (2008).
84. Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247-269 (2008).
85. Wilkins A, Chandran S, Compston A. A role for oligodendrocyte-derived IGF-1 in trophic support of cortical neurons. Glia 36, 48-57 (2001).
86. 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. Neuosci. 23, 4967-4974 (2003).
87. Griffiths I, Klugmann M, Anderson T et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280(5369), 1610-1613 (1998).
88. 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 94(20), 10821-10826 (1997).
89. 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 placebocontrolled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 45(7), 1268-1276 (1995).
90. Trojano M, Pellegrini F, Fuiani A et al. New natural history of interferon-?-treated relapsing multiple sclerosis. Ann. Neurol. 61(4), 300-306 (2007).
91. Yong VW. Differential mechanisms of action of interferon-? and glatiramer aetate in MS. Neurology 59(6), 802-808 (2002).
92. Kieseier BC, Hartung HP. Interferon-? and neuroprotection in multiple sclerosis-facts, hopes and phantasies. Exp. Neurol. 203(1), 1-4 (2007).
93. 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 97(13), 7452-7457 (2000).
94. 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 101(Suppl. 2), 14593-14598 (2004).
95. Ziemssen T, Kümpfel T, Klinkert WE, Neuhaus O, Hohlfeld R. 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 (2002).
96. Filippi M, Rovaris M, Rocca MA, Sormani MP, Wolinsky JS, Comi G; European/Canadian Glatiramer Acetate Study Group. Glatiramer acetate reduces the proportion of new MS lesions evolving into 'black holes'. Neurology 57(4), 731-733 (2001).
97. 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 18(3), 314-319 (2008).
98. Sättler MB, Demmer I, Williams SK et al. Effects of interferon-?-1a on neuronal survival under autoimmune inflammatory conditions. Exp. Neurol. 201(1), 172-181 (2006).
99. Malik O, Compston DA, Scolding NJ. Interferon-? inhibits mitogen induced astrocyte proliferation in vitro. J. Neuroimmunol. 86(2), 155-162 (1998).
100. Bagnato F, Gupta S, Richert ND et al. Effects of interferon-?-1b on black holes in multiple sclerosis over a 6-year period with monthly evaluations. Arch. Neurol. 62(11), 1684-1688 (2005).
101. Filippi M, Rovaris M, Inglese M et al. Interferon-?-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet 364(9444), 1489-1496 (2004).
102. Rosen H, Goetzl EJ. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat. Rev. Immunol. 5(7), 560-570 (2005).
103. Miron VE, Ludwin SK, Darlington PJ et al. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am. J. Pathol. 176(6), 2682-2694 (2010).
104. Kappos L, Radue EW, O'Connor P et al.; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362(5), 387-401 (2010).
105. Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet 340(8825), 952-956 (1992).
106. Claussen MC, Korn T. Immune mechanisms of new therapeutic strategies in MS: teriflunomide. Clin. Immunol. 142(1), 49-56 (2012).
107. Giovannoni G, Comi G, Cook S et al.; CLARITY Study Group. A placebocontrolled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med. 362(5), 416-426 (2010).
108. Kappos L, Gold R, Miller DH et al.; BG-12 Phase IIb Study Investigators. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled Phase IIb study. Lancet 372(9648), 1463-1472 (2008).
109. Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J. Biol. Chem. 284(20), 13291-13295 (2009).
110. Comi G, Jeffery D, Kappos L et al. ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N. Engl. J. Med. 366(11), 1000-1009 (2012).
111. Birnberg T, Jung S. Effect of laquinimod on the dendritic cell compartment. Neurology 72(Suppl. 3), A36 (2009).
112. 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 42(5), 731-739 (2002).
113. Thöne J, Lee D, Seubert S et al. Laquinimod ameliorates experimental autoimmune encephalomyelitis via BDNF-dependent mechanisms. Mult. Scler. 16 (Suppl. 7), S310 (2010).
114. Moreau T, Coles A, Wing M et al. CAMPATH-IH in multiple sclerosis. Mult. Scler. 1(6), 357-365 (1996).
115. Coles AJ, Compston DA, Selmaj KW et al. CAMMS223 Trial Investigators. Alemtuzumab versus interferon-?-1a in early multiple sclerosis. N. Engl. J. Med. 359(17), 1786-1801 (2008).
116. Coles AJ. Alemtuzumab long-term safety and efficacy: five years of the CAMMS223 trial. Mult. Scler. 16, S134-S135 (2010).
117. Jones JL, Anderson JM, Phuah CL et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 133(Pt 8), 2232-2247 (2010).
118. Hao J, Campagnolo D, Liu R et al. Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation. Ann. Neurol. 69(4), 721-734 (2011).
119. Wynn D, Kaufman M, Montalban X et al.; CHOICE investigators. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a Phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon-?. Lancet Neurol. 9(4), 381-390 (2010).
120. Black JA, Liu S, Hains BC, Saab CY, Waxman SG. Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE. Brain 129(Pt 12), 3196-3208 (2006).
121. Black JA, Liu S, Carrithers M, Carrithers LM, Waxman SG. Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine. Ann. Neurol. 62(1), 21-33 (2007).
122. Bechtold DA, Kapoor R, Smith KJ. Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann. Neurol. 55(5), 607-616 (2004).
123. Kapoor R, Furby J, Hayton T et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 9(7), 681-688 (2010).
124. Craner MJ, Damarjian TG, Liu S et al. Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia 49(2), 220-229 (2005).
125. 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. 13(10), 1228-1233 (2007).
126. Brand-Schieber E, Werner P. Calcium channel blockers ameliorate disease in a mouse model of multiple sclerosis. Exp. Neurol. 189(1), 5-9 (2004).
127. Werner P, Pitt D, Raine CS. Glutamate excitotoxicity-a mechanism for axonal damage and oligodendrocyte death in multiple sclerosis? J. Neural Transm. (60), 375-385 (2000).
128. Waxman SG. Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status. Nat. Clin. Pract. Neurol. 4(3), 159-169 (2008).
129. Brines ML, Ghezzi P, Keenan S et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc. Natl Acad. Sci. USA 97(19), 10526-10531 (2000).
130. Buemi M, Cavallaro E, Floccari F et al. The pleiotropic effects of erythropoietin in the central nervous system. J. Neuropathol. Exp. Neurol. 62(3), 228-236 (2003).
131. Sättler MB, Merkler D, Maier K et al. Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis. Cell Death Differ. 11(Suppl. 2), S181-S192 (2004).
132. Ehrenreich H, Fischer B, Norra C et al. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 130(Pt 10), 2577-2588 (2007).
133. Clark AJ, Ware MA, Yazer E, Murray TJ, Lynch ME. Patterns of cannabis use among patients with multiple sclerosis. Neurology 62(11), 2098-2100 (2004).
134. Pryce G, Baker D. Emerging properties of cannabinoid medicines in management of multiple sclerosis. Trends Neurosci. 28(5), 272-276 (2005).
135. Fujiwara M, Egashira N. New perspectives in the studies on endocannabinoid and cannabis: abnormal behaviors associate with CB1 cannabinoid receptor and development of therapeutic application. J. Pharmacol. Sci. 96(4), 362-366 (2004).
136. Kreitzer AC, Regehr WG. Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J. Neurosci. 21(20), RC174 (2001).
137. Pryce G, Ahmed Z, Hankey DJ et al. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126(Pt 10), 2191-2202 (2003).
138. Ligresti A, Cascio MG, Pryce G et al. New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis. Br. J. Pharmacol. 147(1), 83-91 (2006).
139. Neuhaus O, Stüve O, Zamvil SS, Hartung HP. Are statins a treatment option for multiple sclerosis? Lancet Neurol. 3(6), 369-371 (2004).
140. Togha M, Karvigh SA, Nabavi M et al. Simvastatin treatment in patients with relapsing-remitting multiple sclerosis receiving interferon-? 1a: a double-blind randomized-controlled trial. Mult. Scler. 16(7), 848-854 (2010).
141. Klopfleisch S, Merkler D, Schmitz M et al. Negative impact of statins on oligodendrocytes and myelin formation in vitro and in vivo. J. Neurosci. 28(50), 13609-13614 (2008).
142. O'Connor PW, Li D, Freedman MS et al.; Teriflunomide Multiple Sclerosis Trial Group; University of British Columbia MS/MRI Research Group. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 66(6), 894-900 (2006).
143. 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. 49(3), 290-297 (2001).
144. Jacobs L, Rudick R, Simon J. Extended observations on MS patients treated with IM interferon-?-1a (Avonex): implications for modern MS trials and therapeutics. J. Neuroimmunol. 107(2), 167-173 (2000).
145. Kappos L, Freedman MS, Polman CH et al.; BENEFIT Study Group. Effect of early versus delayed interferon-?-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 370(9585), 389-397 (2007).
146. Jacobs LD, Cookfair DL, Rudick RA et al. Intramuscular interferon-?-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann. Neurol. 39(3), 285-294 (1996).
147. Hartung HP, Gonsette R, König N et al.; Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Mitoxantrone in progressive multiple sclerosis: a placebocontrolled, double-blind, randomised, multicentre trial. Lancet 360(9350), 2018-2025 (2002).
148. Edan F, Comi G, Le Page E et al. Mitoxantrone prior to interferon?-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J. Neurol. Neurosurg. Psychiatr. 2018-2025 (2002).
149. Polman CH, O'Connor PW, Havrdova E et al.; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354(9), 899-910 (2006).
150. Luessi F, Zipp F. Neuro aktuell 7/2011, Westermayer Verlag GmbH, p. 28.
151. Hauser SL, Waubant E, Arnold DL et al.; HERMES Trial Group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358(7), 676-688 (2008).
152. Friese MA, Craner MJ, Etzensperger R et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat. Med. 13(12), 1483-1489 (2007).
153. Vergo S, Craner MJ, Etzensperger R et al. Acid-sensing ion channel-1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. Brain 134(Pt 2), 571-584 (2011).
154. Zajicek J, Fox P, Sanders H et al.; UK MS Research Group. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362(9395), 1517-1526 (2003).
155. Maresz K, Pryce G, Ponomarev ED et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat. Med. 13(4), 492-497 (2007).
156. Aktas O, Prozorovski T, Smorodchenko A et al. Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J. Immunol. 173(9), 5794-5800 (2004).
157. Schroeder EK, Kelsey NA, Doyle J et al. Green tea epigallocatechin 3-gallate accumulates in mitochondria and displays a selective antiapoptotic effect against inducers of mitochondrial oxidative stress in neurons. Antioxid. Redox Signal. 11(3), 469-480 (2009).
158. Dörr J, Roth K, Zurbuchen U et al. Tumor-necrosis-factor-related apoptosisinducing-ligand (TRAIL)-mediated death of neurons in living human brain tissue is inhibited by flupirtine-maleate. J. Neuroimmunol. 167(1-2), 204-209 (2005).
159. Sättler MB, Williams SK, Neusch C et al. Flupirtine as neuroprotective add-on therapy in autoimmune optic neuritis. Am. J. Pathol. 173(5), 1496-1507 (2008).
160. Kalkers NF, Barkhof F, Bergers E, van Schijndel R, Polman CH. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult. Scler. 8(6), 532-533 (2002).
161. Angehagen M, Ben-Menachem E, Rönnbäck L, Hansson E. Topiramate protects against glutamate-and kainate-induced neurotoxicity in primary neuronal-astroglial cultures. Epilepsy Res. 54(1), 63-71 (2003).