Mechanisms of Disease Progression



A clear understanding of the mechanisms which underpin disease ­progression is required in order to develop rational therapies for this stage of the disease. Up until a few years ago, the major emphasis in drug development for MS has been to target inflammation and as a result, the pathophysiology of inflammatory demyelination appears better understood than processes occurring during disease progression. However, since the burgeoning of anti-inflammatory therapies for MS and the progress that has been made for relapse prevention, attention has recently been turned to address the issue of disease progression. While representing a major therapeutic challenge, significant progress in understanding the mechanisms of MS disease progression has occurred in recent years.

Specifically, an increased recognition of the importance of axonal injury in progressive disease has emerged. Axonal injury appears to account for much of the disability seen during the progressive phase and, importantly, may be irreversible once certain structural changes have appeared in axons. This is in contrast to myelin injury which is, to some extent, reparable. Thus has emerged the recognition that strategies to protect axons early in the disease are required. Potential strategies to protect axons will be discussed at the end of this chapter after a discussion of the mechanisms of axonal injury in MS.


Axon Demyelination Inflammation Trophic Neuroprotection Oligodendrocyte 


  1. 1.
    Patani R, et al. Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathol Appl Neurobiol. 2007;33(3):277–87.PubMedGoogle Scholar
  2. 2.
    Bjartmar C, et al. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol. 2000;48(6):893–901.PubMedGoogle Scholar
  3. 3.
    Davie CA, et al. 1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1997;63(6):736–42.PubMedGoogle Scholar
  4. 4.
    Leary SM, et al. 1H magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis. J Neurol. 1999;246(11):1023–6.PubMedGoogle Scholar
  5. 5.
    Davie CA, et al. Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain. 1995;118(Pt 6):1583–92.PubMedGoogle Scholar
  6. 6.
    De Stefano N, 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.PubMedGoogle Scholar
  7. 7.
    Gonen O, et al. Total brain N-acetylaspartate: a new measure of disease load in MS. Neurology. 2000;54(1):15–9.PubMedGoogle Scholar
  8. 8.
    Cader S, et al. Discordant white matter N-acetylasparate and diffusion MRI measures suggest that chronic metabolic dysfunction contributes to axonal pathology in multiple sclerosis. Neuroimage. 2007;36(1):19–27.PubMedGoogle Scholar
  9. 9.
    Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol. 2006;5(2):158–70.PubMedGoogle Scholar
  10. 10.
    Amato MP, et al. Neocortical volume decrease in relapsing-remitting MS patients with mild cognitive impairment. Neurology. 2004;63(1):89–93.PubMedGoogle Scholar
  11. 11.
    Tallantyre EC, et al. Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis. Mult Scler. 2010;16(4):406–11.PubMedGoogle Scholar
  12. 12.
    Lovas G, et al. Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain. 2000;123(Pt 2):308–17.PubMedGoogle Scholar
  13. 13.
    DeLuca GC, Ebers GC, Esiri MM. Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts. Brain. 2004;127(Pt 5):1009–18.PubMedGoogle Scholar
  14. 14.
    Ferguson B, et al. Axonal damage in acute multiple sclerosis lesions. Brain. 1997;120(Pt 3):393–9.PubMedGoogle Scholar
  15. 15.
    Trapp BD, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338(5):278–85.PubMedGoogle Scholar
  16. 16.
    Sherriff FE, et al. Markers of axonal injury in post mortem human brain. Acta Neuropathol. 1994;88(5):433–9.PubMedGoogle Scholar
  17. 17.
    Bitsch A, et al. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain. 2000;123(Pt 6):1174–83.PubMedGoogle Scholar
  18. 18.
    Kuhlmann T, 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.PubMedGoogle Scholar
  19. 19.
    Redford EJ, Kapoor R, Smith KJ. Nitric oxide donors reversiblyt block axonal conduction: demyelinated axons are especially susceptible. Brain. 1997;120(Pt 12):2149–57.PubMedGoogle Scholar
  20. 20.
    Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci. 2008;9(11):839–55.PubMedGoogle Scholar
  21. 21.
    Kremenchutzky M, et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006;129(Pt 3):584–94.PubMedGoogle Scholar
  22. 22.
    Confavreux C, et al. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343(20):1430–8.PubMedGoogle Scholar
  23. 23.
    Scalfari A, et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010;133(Pt 7):1914–29.PubMedGoogle Scholar
  24. 24.
    Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain. 2006;129(Pt 3): 595–605.PubMedGoogle Scholar
  25. 25.
    Vukusic S, Confavreux C. Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis. J Neurol Sci. 2003;206(2):135–7.PubMedGoogle Scholar
  26. 26.
    Jacobs LD. 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.PubMedGoogle Scholar
  27. 27.
    Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. 1998;352(9139):1498–504.Google Scholar
  28. 28.
    Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993;43(4):655–61.Google Scholar
  29. 29.
    Johnson KP. 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.PubMedGoogle Scholar
  30. 30.
    Rojas JI, et al. Interferon beta for primary progressive multiple sclerosis. Cochrane Database Syst Rev. 2010;(1):CD006643.Google Scholar
  31. 31.
    La Mantia L, Munari LM, Lovati R. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2010;(5):CD004678.Google Scholar
  32. 32.
    Coles AJ, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006;253(1):98–108.PubMedGoogle Scholar
  33. 33.
    Moreau T, et al. CAMPATH-IH in multiple sclerosis. Mult Scler. 1996;1(6):357–65.PubMedGoogle Scholar
  34. 34.
    Coles AJ. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359(17):1786–801.PubMedGoogle Scholar
  35. 35.
    Bruck W. The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage. J Neurol. 2005;252 Suppl 5:v3–9.PubMedGoogle Scholar
  36. 36.
    Lucchinetti C, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47(6):707–17.PubMedGoogle Scholar
  37. 37.
    Hohlfeld R, Wekerle H. Immunological update on multiple sclerosis. Curr Opin Neurol. 2001;14(3):299–304.PubMedGoogle Scholar
  38. 38.
    Hohlfeld R, Wekerle H. Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: from pipe dreams to (therapeutic) pipelines. Proc Natl Acad Sci USA. 2004;101 Suppl 2:14599–606.PubMedGoogle Scholar
  39. 39.
    Gold R, Linington C, Lassmann H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain. 2006;129(Pt 8):1953–71.PubMedGoogle Scholar
  40. 40.
    Matusevicius D, et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler. 1999;5(2):101–4.PubMedGoogle Scholar
  41. 41.
    Bettini M, Vignali DA. Regulatory T cells and inhibitory cytokines in autoimmunity. Curr Opin Immunol. 2009;21(6):612–8.PubMedGoogle Scholar
  42. 42.
    Neumann H, et al. Induction of MHC class I genes in neurons. Science. 1995;269(5223):549–52.PubMedGoogle Scholar
  43. 43.
    Medana I, et al. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am J Pathol. 2001;159(3):809–15.PubMedGoogle Scholar
  44. 44.
    Lennon VA, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106–12.PubMedGoogle Scholar
  45. 45.
    Mathey EK, et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med. 2007;204(10):2363–72.PubMedGoogle Scholar
  46. 46.
    Howell OW, et al. Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain. 2006;129(Pt 12):3173–85.PubMedGoogle Scholar
  47. 47.
    Bartos A, et al. Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis. J Neurol. 2007;254(1):20–5.PubMedGoogle Scholar
  48. 48.
    Teunissen CE, Dijkstra C, Polman C. Biological markers in CSF and blood for axonal degeneration in multiple sclerosis. Lancet Neurol. 2005;4(1):32–41.PubMedGoogle Scholar
  49. 49.
    Smith KJ, Lassmann H. The role of nitric oxide in multiple sclerosis. Lancet Neurol. 2002;1(4):232–41.PubMedGoogle Scholar
  50. 50.
    Bagasra O, et al. Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. Proc Natl Acad Sci USA. 1995;92(26):12041–5.PubMedGoogle Scholar
  51. 51.
    Hill KE, et al. Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage. J Neuroimmunol. 2004;151(1–2):171–9.PubMedGoogle Scholar
  52. 52.
    Gray E, et al. Peroxisome proliferator-activated receptor-alpha agonists protect cortical neurons from inflammatory mediators and improve peroxisomal function. Eur J Neurosci. 2011;33(8):1421–32.PubMedGoogle Scholar
  53. 53.
    Gibbons HM, Dragunow M. Microglia induce neural cell death via a proximity-dependent mechanism involving nitric oxide. Brain Res. 2006;1084(1):1–15.PubMedGoogle Scholar
  54. 54.
    Smith KJ, et al. Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol. 2001;49(4):470–6.PubMedGoogle Scholar
  55. 55.
    Kapoor R, et al. Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann Neurol. 2003;53(2):174–80.PubMedGoogle Scholar
  56. 56.
    Ghatan S, et al. p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons. J Cell Biol. 2000;150(2):335–47.PubMedGoogle Scholar
  57. 57.
    Bal-Price A, Brown GC. Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci. 2001;21(17):6480–91.PubMedGoogle Scholar
  58. 58.
    Golde S, et al. Different pathways for iNOS-mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression. J Neurochem. 2002;82(2):269–82.PubMedGoogle Scholar
  59. 59.
    Brown GC, Borutaite V. Nitric oxide inhibition of mitochondrial respiration and its role in cell death. Free Radic Biol Med. 2002;33(11):1440–50.PubMedGoogle Scholar
  60. 60.
    Wilkins A, Compston A. Trophic factors attenuate nitric oxide mediated neuronal and axonal injury in vitro: roles and interactions of mitogen-activated protein kinase signalling pathways. J Neurochem. 2005;92(6):1487–96.PubMedGoogle Scholar
  61. 61.
    Hares K, et al. Neurofilament bot blot assays: novel means of assessing axon viability in culture. J Neurosci Methods. 2011;198(2):195–203.PubMedGoogle Scholar
  62. 62.
    Calabrese V, et al. Nitric oxide synthase is present in the cerebrospinal fluid of patients with active multiple sclerosis and is associated with increases in cerebrospinal fluid protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels. J Neurosci Res. 2002;70(4):580–7.PubMedGoogle Scholar
  63. 63.
    Calabresi PA, et al. Cytokine gene expression in cells derived from CSF of multiple sclerosis patients. J Neuroimmunol. 1998;89(1–2):198–205.PubMedGoogle Scholar
  64. 64.
    Hofman FM, et al. Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med. 1989;170(2):607–12.PubMedGoogle Scholar
  65. 65.
    Rieckmann P, et al. Tumor necrosis factor-alpha messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity. Ann Neurol. 1995;37(1):82–8.PubMedGoogle Scholar
  66. 66.
    Jurewicz A, et al. Tumour necrosis factor-induced death of adult human oligodendrocytes is mediated by apoptosis inducing factor. Brain. 2005;128(Pt 11):2675–88.PubMedGoogle Scholar
  67. 67.
    Liu J, et al. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat Med. 1998;4(1):78–83.PubMedGoogle Scholar
  68. 68.
    Dopp JM, et al. Expression of the p75 TNF receptor is linked to TNF-induced NFkappaB translocation and oxyradical neutralization in glial cells. Neurochem Res. 2002;27(11):1535–42.PubMedGoogle Scholar
  69. 69.
    Gary DS, et al. Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor. J Cereb Blood Flow Metab. 1998;18(12):1283–7.PubMedGoogle Scholar
  70. 70.
    TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology. 1999;53(3):457–65.Google Scholar
  71. 71.
    van Oosten BW, et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology. 1996;47(6):1531–4.PubMedGoogle Scholar
  72. 72.
    Hohlfeld R, et al. The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis. Neurol Sci. 2006;27 Suppl 1:S1–7.PubMedGoogle Scholar
  73. 73.
    Stadelmann C, et al. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain. 2002;125(Pt 1):75–85.PubMedGoogle Scholar
  74. 74.
    Jones JL, et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain. 2010;133(Pt 8):2232–47.PubMedGoogle Scholar
  75. 75.
    Foote AK, Blakemore WF. Inflammation stimulates remyelination in areas of chronic demyelination. Brain. 2005;128(Pt 3):528–39.PubMedGoogle Scholar
  76. 76.
    Brady ST, et al. Formation of compact myelin is required for maturation of the axonal cytoskeleton. J Neurosci. 1999;19(17):7278–88.PubMedGoogle Scholar
  77. 77.
    Sanchez I, et al. Local control of neurofilament accumulation during radial growth of myelinating axons in vivo Selective role of site-specific phosphorylation. J Cell Biol. 2000;151(5):1013–24.PubMedGoogle Scholar
  78. 78.
    Kirkpatrick LL, et al. Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons. J Neurosci. 2001;21(7):2288–97.PubMedGoogle Scholar
  79. 79.
    Griffiths I, et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science. 1998;280(5369):1610–3.PubMedGoogle Scholar
  80. 80.
    Edgar JM, et al. Age-related axonal and myelin changes in the rumpshaker mutation of the Plp gene. Acta Neuropathol. 2004;107(4):331–5.PubMedGoogle Scholar
  81. 81.
    Yin X, et al. Evolution of a neuroprotective function of central nervous system myelin. J Cell Biol. 2006;172(3):469–78.PubMedGoogle Scholar
  82. 82.
    Lappe-Siefke C, et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet. 2003;33(3):366–74.PubMedGoogle Scholar
  83. 83.
    Wilkins A, et al. Slowly progressive axonal degeneration in a rat model of chronic, nonimmune-mediated demyelination. J Neuropathol Exp Neurol. 2010;69(12):1256–69.PubMedGoogle Scholar
  84. 84.
    Irvine KA, Blakemore WF. Remyelination protects axons from demyelination-associated axon degeneration. Brain. 2008;131(Pt 6):1464–77.PubMedGoogle Scholar
  85. 85.
    Yool DA, et al. The proteolipid protein gene and myelin disorders in man and animal models. Hum Mol Genet. 2000;9(6):987–92.PubMedGoogle Scholar
  86. 86.
    Garbern JY, et al. Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain. 2002;125(Pt 3):551–61.PubMedGoogle Scholar
  87. 87.
    Bonavita S, et al. Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations. Neurology. 2001;56(6):785–8.PubMedGoogle Scholar
  88. 88.
    Shinar Y, McMorris FA. Developing oligodendroglia express mRNA for insulin-like growth factor-I, a regulator of oligodendrocyte development. J Neurosci Res. 1995;42(4):516–27.PubMedGoogle Scholar
  89. 89.
    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.PubMedGoogle Scholar
  90. 90.
    Dai X, Qu P, Dreyfus CF. Neuronal signals regulate neurotrophin expression in oligodendrocytes of the basal forebrain. Glia. 2001;34(3):234–9.PubMedGoogle Scholar
  91. 91.
    Wilkins A, 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.PubMedGoogle Scholar
  92. 92.
    Craner MJ. Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain. 2004;127(Pt 2):294–303.PubMedGoogle Scholar
  93. 93.
    Kaplan MR, et al. Induction of sodium channel clustering by oligodendrocytes. Nature. 1997;386(6626):724–8.PubMedGoogle Scholar
  94. 94.
    Rasband MN, et al. Dysregulation of axonal sodium channel isoforms after adult-onset chronic demyelination. J Neurosci Res. 2003;73(4):465–70.PubMedGoogle Scholar
  95. 95.
    Craner MJ. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci USA. 2004;101(21):8168–73.PubMedGoogle Scholar
  96. 96.
    Kapoor R, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 2010;9(7):681–8.PubMedGoogle Scholar
  97. 97.
    Olsen NK, et al. Leber’s hereditary optic neuropathy associated with a disorder indistinguishable from multiple sclerosis in a male harbouring the mitochondrial DNA 11778 mutation. Acta Neurol Scand. 1995;91(5):326–9.PubMedGoogle Scholar
  98. 98.
    Stys PK. White matter injury mechanisms. Curr Mol Med. 2004;4(2):113–30.PubMedGoogle Scholar
  99. 99.
    Lu F, et al. Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J Neurol Sci. 2000;177(2):95–103.PubMedGoogle Scholar
  100. 100.
    Mahad DJ, et al. Mitochondrial changes within axons in multiple sclerosis. Brain. 2009;132(Pt 5):1161–74.PubMedGoogle Scholar
  101. 101.
    Dutta R, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol. 2006;59(3):478–89.PubMedGoogle Scholar
  102. 102.
    Kim JY, et al. HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage. Nat Neurosci. 2010;13(2):180–9.PubMedGoogle Scholar
  103. 103.
    Stagi M, et al. Unloading kinesin transported cargoes from the tubulin track via the inflammatory c-Jun N-terminal kinase pathway. FASEB J. 2006;20(14):2573–5.PubMedGoogle Scholar
  104. 104.
    DeLuca GC, et al. The contribution of demyelination to axonal loss in multiple sclerosis. Brain. 2006;129(Pt 6):1507–16.PubMedGoogle Scholar
  105. 105.
    Stadelmann C, et al. Cortical pathology in multiple sclerosis. Curr Opin Neurol. 2008;21(3):229–34.PubMedGoogle Scholar
  106. 106.
    Magliozzi R, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130(Pt 4):1089–104.PubMedGoogle Scholar
  107. 107.
    Peterson JW, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50(3):389–400.PubMedGoogle Scholar
  108. 108.
    Serafini B, et al. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004;14(2):164–74.PubMedGoogle Scholar
  109. 109.
    Kooi EJ, et al. Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis. J Neuropathol Exp Neurol. 2009;68(9):1021–8.PubMedGoogle Scholar
  110. 110.
    Ascherio A, Munger KL. Epstein-barr virus infection and multiple sclerosis: a review. J Neuroimmune Pharmacol. 2010;5(3):271–7.PubMedGoogle Scholar
  111. 111.
    Coles AJ, et al. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011;10(4):338–48.PubMedGoogle Scholar
  112. 112.
    Gilgun-Sherki Y, et al. Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis. Brain Res. 2003;989(2):196–204.PubMedGoogle Scholar
  113. 113.
    Black JA, et al. Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE. Brain. 2006;129(Pt 12):3196–208.PubMedGoogle Scholar
  114. 114.
    Zajicek JP, Apostu VI. Role of cannabinoids in multiple sclerosis. CNS Drugs. 2011;25(3):187–201.PubMedGoogle Scholar
  115. 115.
    Nikodemova M, et al. Minocycline attenuates experimental autoimmune encephalomyelitis in rats by reducing T cell infiltration into the spinal cord. J Neuroimmunol. 2010;219(1–2):33–7.PubMedGoogle Scholar
  116. 116.
    Wilkins A, et al. Minocycline attenuates nitric oxide-mediated neuronal and axonal destruction in vitro. Neuron Glia Biol. 2004;1(3):297–305.PubMedGoogle Scholar
  117. 117.
    Metz LM, et al. Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol. 2004;55(5):756.PubMedGoogle Scholar
  118. 118.
    Kassmann CM, et al. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat Genet. 2007;39(8):969–76.PubMedGoogle Scholar
  119. 119.
    Uccelli A, Prockop DJ. Why should mesenchymal stem cells (MSCs) cure autoimmune diseases? Curr Opin Immunol. 2010;22(6):768–74.PubMedGoogle Scholar
  120. 120.
    Scolding N, et al. Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain. 1998;121(Pt 12):2221–8.PubMedGoogle Scholar
  121. 121.
    Kemp K, et al. Fusion between human mesenchymal stem cells and rodent cerebellar Purkinje cells. Neuropathol Appl Neurobiol. 2011;37(2):166–78.PubMedGoogle Scholar
  122. 122.
    Kemp K, et al. Inflammatory cytokine induced regulation of superoxide dismutase 3 expression by human mesenchymal stem cells. Stem Cell Rev. 2010;6(4):548–59.PubMedGoogle Scholar
  123. 123.
    Lanza C, et al. Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo. J Neurochem. 2009;110(5):1674–84.PubMedGoogle Scholar
  124. 124.
    Pitt D, Werner P, and Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med. 2000;6(1):67–70.PubMedGoogle Scholar
  125. 125.
    Werner P, Pitt D, and Raine CS. Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann Neurol. 2001;50(2):169–80.PubMedGoogle Scholar
  126. 126.
    Li S, and Stys PK. Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter. J Neurosci. 2000;20(3):1190–8.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  1. 1.Department of NeurologyFrenchay HospitalBristolUK

Personalised recommendations