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  • Review Article
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Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis

Nature Reviews Neurology volume 10, pages 225–238 (2014)Cite this article

Subjects

Key Points

  • Neuronal and axonal degeneration in multiple sclerosis (MS) is a slow process initiated by acute lymphocytic inflammation, and subsequently driven by chronically smouldering, diffuse parenchymal myeloid and meningeal lymphocytic inflammation

  • Oxidative stress, mitochondrial injury and subsequent ion channel dysfunction secondary to chronic inflammation seem to have a constant impact on neurons and axons, leading to their demise during progressive MS

  • Several ion channels show compensatory changes in response to the inflammatory stimulus by altering their relative distribution in the neuron—a process that eventually becomes maladaptive and perpetuates neuroaxonal injury

  • Several neuroprotective pathways have been identified in MS, but these pathways become overridden, resulting in neuronal degeneration that is probably mediated by the initiation of apoptosis and Wallerian degeneration

  • The balance between continuous inflammatory stressors and intrinsic buffering mechanisms depends partly on age, sex and genetic factors, which eventually determine the clinical course of MS

  • In an animal model of MS, few molecular targets with proven neuroprotective properties that are separable from their impact on inflammatory responses have been identified; these molecules include CyPD, ASIC1 and TRPM4

Abstract

Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the CNS, and imposes major burdens on young lives. Great progress has been made in understanding and moderating the acute inflammatory components of MS, but the pathophysiological mechanisms of the concomitant neurodegeneration—which causes irreversible disability—are still not understood. Chronic inflammatory processes that continuously disturb neuroaxonal homeostasis drive neurodegeneration, so the clinical outcome probably depends on the balance of stressor load (inflammation) and any remaining capacity for neuronal self-protection. Hence, suitable drugs that promote the latter state are sorely needed. With the aim of identifying potential novel therapeutic targets in MS, we review research on the pathological mechanisms of neuroaxonal dysfunction and injury, such as altered ion channel activity, and the endogenous neuroprotective pathways that counteract oxidative stress and mitochondrial dysfunction. We focus on mechanisms inherent to neurons and their axons, which are separable from those acting on inflammatory responses and might, therefore, represent bona fide neuroprotective drug targets with the capability to halt MS progression.

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Figure 1: Clinical correlates of neurodegeneration in MS.
Figure 2: Radiological correlates of neurodegeneration in multiple sclerosis.
Figure 3: Pathological correlates of neurodegeneration in MS.
Figure 4: Cascades leading to inflammation-induced neuroaxonal injury.
Figure 5: Neuronal injury and counteracting pathways in chronic CNS inflammation.

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References

  1. Compston, A. & Coles, A. Multiple sclerosis. Lancet 372, 1502–1517 (2008).

    CAS  PubMed  Google Scholar 

  2. Weiner, H. L. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J. Neurol. 255 (Suppl. 1), 3–11 (2008).

    CAS  PubMed  Google Scholar 

  3. Funfschilling, U. et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485, 517–521 (2012).

    PubMed  PubMed Central  Google Scholar 

  4. Lee, Y. et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443–448 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Frischer, J. M. et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132, 1175–1189 (2009).

    PubMed  PubMed Central  Google Scholar 

  6. Kornek, B. et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol. 157, 267–276 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Kutzelnigg, A. et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128, 2705–2712 (2005).

    PubMed  Google Scholar 

  8. DeLuca, G. C., Ebers, G. C. & Esiri, M. M. Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts. Brain 127, 1009–1018 (2004).

    CAS  PubMed  Google Scholar 

  9. Bitsch, A., Schuchardt, J., Bunkowski, S., Kuhlmann, T. & Bruck, W. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123, 1174–1183 (2000).

    PubMed  Google Scholar 

  10. DeLuca, G. C., Williams, K., Evangelou, N., Ebers, G. C. & Esiri, M. M. The contribution of demyelination to axonal loss in multiple sclerosis. Brain 129, 1507–1516 (2006).

    CAS  PubMed  Google Scholar 

  11. Scalfari, A., Neuhaus, A., Daumer, M., Muraro, P. A. & Ebers, G. C. Onset of secondary progressive phase and long-term evolution of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 85, 67–75 (2014).

    PubMed  Google Scholar 

  12. Confavreux, C., Vukusic, S., Moreau, T. & Adeleine, P. Relapses and progression of disability in multiple sclerosis. N. Engl. J. Med. 343, 1430–1438 (2000).

    CAS  PubMed  Google Scholar 

  13. Scalfari, A. et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain 133, 1914–1929 (2010).

    PubMed  PubMed Central  Google Scholar 

  14. Scalfari, A. et al. Early relapses, onset of progression, and late outcome in multiple sclerosis. JAMA Neurol. 70, 214–222 (2013).

    PubMed  Google Scholar 

  15. Kappos, L. et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 8, 987–997 (2009).

    CAS  PubMed  Google Scholar 

  16. Shirani, A. et al. Association between use of interferon beta and progression of disability in patients with relapsing–remitting multiple sclerosis. JAMA 308, 247–256 (2012).

    CAS  PubMed  Google Scholar 

  17. Haghikia, A., Hohlfeld, R., Gold, R. & Fugger, L. Therapies for multiple sclerosis: translational achievements and outstanding needs. Trends Mol. Med. 19, 309–319 (2013).

    CAS  PubMed  Google Scholar 

  18. Barkhof, F., Calabresi, P. A., Miller, D. H. & Reingold, S. C. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat. Rev. Neurol. 5, 256–266 (2009).

    PubMed  Google Scholar 

  19. Chard, D. T. et al. Brain atrophy in clinically early relapsing–remitting multiple sclerosis. Brain 125, 327–337 (2002).

    CAS  PubMed  Google Scholar 

  20. Miller, D. H., Barkhof, F., Frank, J. A., Parker, G. J. & Thompson, A. J. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 125, 1676–1695 (2002).

    PubMed  Google Scholar 

  21. Petzold, A. et al. Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 9, 921–932 (2010).

    PubMed  Google Scholar 

  22. Kuhle, J. et al. Neurofilament heavy chain in CSF correlates with relapses and disability in multiple sclerosis. Neurology 76, 1206–1213 (2011).

    CAS  PubMed  Google Scholar 

  23. Gunnarsson, M. et al. Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann. Neurol. 69, 83–89 (2011).

    CAS  PubMed  Google Scholar 

  24. Popescu, B. F. & Lucchinetti, C. F. Pathology of demyelinating diseases. Annu. Rev. Pathol. 7, 185–217 (2012).

    CAS  PubMed  Google Scholar 

  25. Bjartmar, C., Kidd, G., Mörk, S., Rudick, R. & Trapp, B. D. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann. Neurol. 48, 893–901 (2000).

    CAS  PubMed  Google Scholar 

  26. Dziedzic, T. et al. Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis. Brain Pathol. 20, 976–985 (2010).

    PubMed  Google Scholar 

  27. Peterson, J. W., Bö, L., Mörk, S., Chang, A. & Trapp, B. D. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50, 389–400 (2001).

    CAS  PubMed  Google Scholar 

  28. Vercellino, M. et al. Grey matter pathology in multiple sclerosis. J. Neuropathol. Exp. Neurol. 64, 1101–1107 (2005).

    PubMed  Google Scholar 

  29. Lucchinetti, C. F. et al. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 365, 2188–2197 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kutzelnigg, A. et al. Widespread demyelination in the cerebellar cortex in multiple sclerosis. Brain Pathol. 17, 38–44 (2007).

    PubMed  Google Scholar 

  31. Choi, S. R. et al. Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. Brain 135, 2925–2937 (2012).

    PubMed  Google Scholar 

  32. Howell, O. W. et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 134, 2755–2771 (2011).

    PubMed  Google Scholar 

  33. DeLuca, G. C. et al. Casting light on multiple sclerosis heterogeneity: the role of HLA-DRB1 on spinal cord pathology. Brain 136, 1025–1034 (2013).

    PubMed  Google Scholar 

  34. The International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357, 851–862 (2007).

  35. Baranzini, S. E. et al. Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum. Mol. Genet. 18, 767–778 (2009).

    CAS  PubMed  Google Scholar 

  36. Brynedal, B. et al. MGAT5 alters the severity of multiple sclerosis. J. Neuroimmunol. 220, 120–124 (2010).

    CAS  PubMed  Google Scholar 

  37. International Multiple Sclerosis Genetics Consortium. Genome-wide association study of severity in multiple sclerosis. Genes Immun. 12, 615–625 (2011).

  38. Baranzini, S. E. et al. Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis. Brain 133, 2603–2611 (2010).

    PubMed  PubMed Central  Google Scholar 

  39. Friese, M. A. et al. The value of animal models for drug development in multiple sclerosis. Brain 129, 1940–1952 (2006).

    PubMed  Google Scholar 

  40. Haider, L. et al. Oxidative damage in multiple sclerosis lesions. Brain 134, 1914–1924 (2011).

    PubMed  PubMed Central  Google Scholar 

  41. Zeis, T. et al. Molecular changes in white matter adjacent to an active demyelinating lesion in early multiple sclerosis. Brain Pathol. 19, 459–466 (2009).

    CAS  PubMed  Google Scholar 

  42. Nikic, I. et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med. 17, 495–499 (2011).

    CAS  PubMed  Google Scholar 

  43. Fischer, M. T. et al. Disease-specific molecular events in cortical multiple sclerosis lesions. Brain 136, 1799–1815 (2013).

    PubMed  PubMed Central  Google Scholar 

  44. Gray, E., Thomas, T. L., Betmouni, S., Scolding, N. & Love, S. Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis. Brain Pathol. 18, 86–95 (2008).

    PubMed  Google Scholar 

  45. Fischer, M. T. et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 135, 886–899 (2012).

    PubMed  PubMed Central  Google Scholar 

  46. Li, S., Vana, A. C., Ribeiro, R. & Zhang, Y. Distinct role of nitric oxide and peroxynitrite in mediating oligodendrocyte toxicity in culture and in experimental autoimmune encephalomyelitis. Neuroscience 184, 107–119 (2011).

    CAS  PubMed  Google Scholar 

  47. Smith, K. J., Kapoor, R., Hall, S. M. & Davies, M. Electrically active axons degenerate when exposed to nitric oxide. Ann. Neurol. 49, 470–476 (2001).

    CAS  PubMed  Google Scholar 

  48. Hametner, S. et al. Iron and neurodegeneration in the multiple sclerosis brain. Ann. Neurol. 74, 846–861 (2013).

    Google Scholar 

  49. Rathore, K. I. et al. Ceruloplasmin protects injured spinal cord from iron-mediated oxidative damage. J. Neurosci. 28, 12736–12747 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Craelius, W., Migdal, M. W., Luessenhop, C. P., Sugar, A. & Mihalakis, I. Iron deposits surrounding multiple sclerosis plaques. Arch. Pathol. Lab. Med. 106, 397–399 (1982).

    CAS  PubMed  Google Scholar 

  51. Bagnato, F. et al. Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla. Brain 134, 3602–3615 (2011).

    PubMed  Google Scholar 

  52. Lopes, K. O., Sparks, D. L. & Streit, W. J. Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity. Glia 56, 1048–1060 (2008).

    PubMed  Google Scholar 

  53. Lassmann, H., van Horssen, J. & Mahad, D. Progressive multiple sclerosis: pathology and pathogenesis. Nat. Rev. Neurol. 8, 647–656 (2012).

    CAS  PubMed  Google Scholar 

  54. Nathoo, N. et al. Susceptibility-weighted imaging in the experimental autoimmune encephalomyelitis model of multiple sclerosis indicates elevated deoxyhemoglobin, iron deposition and demyelination. Mult. Scler. 19, 721–731 (2013).

    PubMed  Google Scholar 

  55. Kensler, T. W., Wakabayashi, N. & Biswal, S. Cell survival responses to environmental stresses via the Keap1–Nrf2–ARE pathway. Annu. Rev. Pharmacol. Toxicol. 47, 89–116 (2007).

    CAS  PubMed  Google Scholar 

  56. van Horssen, J. et al. Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic. Biol. Med. 45, 1729–1737 (2008).

    CAS  PubMed  Google Scholar 

  57. Chora, A. A. et al. Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation. J. Clin. Invest. 117, 438–447 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Pennisi, G. et al. Redox regulation of cellular stress response in multiple sclerosis. Biochem. Pharmacol. 82, 1490–1499 (2011).

    CAS  PubMed  Google Scholar 

  59. Johnson, D. A., Amirahmadi, S., Ward, C., Fabry, Z. & Johnson, J. A. The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicol. Sci. 114, 237–246 (2010).

    CAS  PubMed  Google Scholar 

  60. Linker, R. A. et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134, 678–692 (2011).

    PubMed  Google Scholar 

  61. Ghoreschi, K. et al. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J. Exp. Med. 208, 2291–2303 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Schilling, S., Goelz, S., Linker, R., Luehder, F. & Gold, R. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin. Exp. Immunol. 145, 101–107 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).

    CAS  PubMed  Google Scholar 

  64. Trapp, B. D. & Stys, P. K. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 8, 280–291 (2009).

    CAS  PubMed  Google Scholar 

  65. Wallace, D. C., Fan, W. & Procaccio, V. Mitochondrial energetics and therapeutics. Annu. Rev. Pathol. 5, 297–348 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

    CAS  PubMed  Google Scholar 

  67. Echaniz-Laguna, A. et al. POLG1 variations presenting as multiple sclerosis. Arch. Neurol. 67, 1140–1143 (2010).

    PubMed  Google Scholar 

  68. Kim, J. Y. et al. HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage. Nat. Neurosci. 13, 180–189 (2010).

    PubMed  Google Scholar 

  69. Shindler, K. S. et al. Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J. Neuroophthalmol. 30, 328–339 (2010).

    PubMed  PubMed Central  Google Scholar 

  70. Park, S. J. et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148, 421–433 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Forte, M. et al. Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc. Natl Acad. Sci. USA 104, 7558–7563 (2007).

    CAS  PubMed  Google Scholar 

  72. Friese, M. A. et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat. Med. 13, 1483–1489 (2007).

    CAS  PubMed  Google Scholar 

  73. Aboul-Enein, F. et al. Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J. Neuropathol. Exp. Neurol. 62, 25–33 (2003).

    CAS  PubMed  Google Scholar 

  74. Graumann, U., Reynolds, R., Steck, A. J. & Schaeren-Wiemers, N. Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol. 13, 554–573 (2003).

    CAS  PubMed  Google Scholar 

  75. Howarth, C., Gleeson, P. & Attwell, D. Updated energy budgets for neural computation in the neocortex and cerebellum. J. Cereb. Blood Flow Metab. 32, 1222–1232 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Paling, D. et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain 136, 2305–2317 (2013).

    PubMed  Google Scholar 

  77. Young, E. A. et al. Imaging correlates of decreased axonal Na+/K+ ATPase in chronic multiple sclerosis lesions. Ann. Neurol. 63, 428–435 (2008).

    PubMed  Google Scholar 

  78. Craner, M. J. et al. 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 101, 8168–8173 (2004).

    CAS  PubMed  Google Scholar 

  79. Alle, H., Roth, A. & Geiger, J. R. Energy-efficient action potentials in hippocampal mossy fibers. Science 325, 1405–1408 (2009).

    CAS  PubMed  Google Scholar 

  80. Carter, B. C. & Bean, B. P. Sodium entry during action potentials of mammalian neurons: incomplete inactivation and reduced metabolic efficiency in fast-spiking neurons. Neuron 64, 898–909 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Hodgkin, A. The optimum density of sodium channels in an unmyelinated nerve. Philos. Trans. R. Soc. Lond. B Biol. Sci. 270, 297–300 (1975).

    CAS  PubMed  Google Scholar 

  82. Craner, M. J., Hains, B. C., Lo, A. C., Black, J. A. & Waxman, S. G. Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain 127, 294–303 (2004).

    PubMed  Google Scholar 

  83. O'Malley, H. A., Shreiner, A. B., Chen, G. H., Huffnagle, G. B. & Isom, L. L. Loss of Na+ channel β2 subunits is neuroprotective in a mouse model of multiple sclerosis. Mol. Cell. Neurosci. 40, 143–155 (2009).

    CAS  PubMed  Google Scholar 

  84. Bechtold, D. A., Kapoor, R. & Smith, K. J. Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann. Neurol. 55, 607–616 (2004).

    CAS  PubMed  Google Scholar 

  85. Morsali, D. et al. Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain 136, 1067–1082 (2013).

    PubMed  Google Scholar 

  86. Black, J. A., Liu, S., Carrithers, M., Carrithers, L. M. & Waxman, S. G. Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine. Ann. Neurol. 62, 21–33 (2007).

    CAS  PubMed  Google Scholar 

  87. Lo, A. C., Saab, C. Y., Black, J. A. & Waxman, S. G. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J. Neurophysiol. 90, 3566–3571 (2003).

    CAS  PubMed  Google Scholar 

  88. Bechtold, D. A. et al. Axonal protection achieved in a model of multiple sclerosis using lamotrigine. J. Neurol. 253, 1542–1551 (2006).

    PubMed  Google Scholar 

  89. Craner, M. J. et al. Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia 49, 220–229 (2005).

    PubMed  Google Scholar 

  90. Kapoor, R. et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 9, 681–688 (2010).

    CAS  PubMed  Google Scholar 

  91. Shields, S. D. et al. A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis. Ann. Neurol. 71, 186–194 (2012).

    PubMed  Google Scholar 

  92. Moran, M. M., McAlexander, M. A., Biro, T. & Szallasi, A. Transient receptor potential channels as therapeutic targets. Nat. Rev. Drug Discov. 10, 601–620 (2011).

    CAS  PubMed  Google Scholar 

  93. Guinamard, R., Demion, M. & Launay, P. Physiological roles of the TRPM4 channel extracted from background currents. Physiology (Bethesda) 25, 155–164 (2010).

    CAS  Google Scholar 

  94. Schattling, B. et al. TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med. 18, 1805–1811 (2012).

    CAS  PubMed  Google Scholar 

  95. Dunn, J. & Blight, A. Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis. Curr. Med. Res. Opin. 27, 1415–1423 (2011).

    CAS  PubMed  Google Scholar 

  96. Jukkola, P. I., Lovett-Racke, A. E., Zamvil, S. S. & Gu, C. K+ channel alterations in the progression of experimental autoimmune encephalomyelitis. Neurobiol. Dis. 47, 280–293 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Beraud, E. et al. Block of neural Kv1.1 potassium channels for neuroinflammatory disease therapy. Ann. Neurol. 60, 586–596 (2006).

    CAS  PubMed  Google Scholar 

  98. Mathie, A. & Veale, E. L. Therapeutic potential of neuronal two-pore domain potassium-channel modulators. Curr. Opin. Investig. Drugs 8, 555–562 (2007).

    CAS  PubMed  Google Scholar 

  99. Bittner, S. et al. TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system. Brain 132, 2501–2516 (2009).

    PubMed  PubMed Central  Google Scholar 

  100. Bittner, S. et al. The TASK1 channel inhibitor A293 shows efficacy in a mouse model of multiple sclerosis. Exp. Neurol. 238, 149–155 (2012).

    CAS  PubMed  Google Scholar 

  101. Brand-Schieber, E. & Werner, P. Calcium channel blockers ameliorate disease in a mouse model of multiple sclerosis. Exp. Neurol. 189, 5–9 (2004).

    CAS  PubMed  Google Scholar 

  102. Waxman, S. G. & Ritchie, J. M. Molecular dissection of the myelinated axon. Ann. Neurol. 33, 121–136 (1993).

    CAS  PubMed  Google Scholar 

  103. Kornek, B. et al. Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain 124, 1114–1124 (2001).

    CAS  PubMed  Google Scholar 

  104. Gadjanski, I. et al. Role of N-type voltage-dependent calcium channels in autoimmune optic neuritis. Ann. Neurol. 66, 81–93 (2009).

    CAS  PubMed  Google Scholar 

  105. Stirling, D. P. & Stys, P. K. Mechanisms of axonal injury: internodal nanocomplexes and calcium deregulation. Trends Mol. Med. 16, 160–170 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Hardingham, G. E. & Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11, 682–696 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Mahad, D. J. et al. Mitochondrial changes within axons in multiple sclerosis. Brain 132, 1161–1174 (2009).

    PubMed  PubMed Central  Google Scholar 

  108. Grasselli, G. et al. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis. Br. J. Pharmacol. 168, 502–517 (2013).

    CAS  PubMed  Google Scholar 

  109. Sarchielli, P., Greco, L., Floridi, A. & Gallai, V. Excitatory amino acids and multiple sclerosis: evidence from cerebrospinal fluid. Arch. Neurol. 60, 1082–1088 (2003).

    PubMed  Google Scholar 

  110. Piani, D., Frei, K., Do, K. Q., Cuenod, M. & Fontana, A. Murine brain macrophages induced NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci. Lett. 133, 159–162 (1991).

    CAS  PubMed  Google Scholar 

  111. Newcombe, J. et al. Glutamate receptor expression in multiple sclerosis lesions. Brain Pathol. 18, 52–61 (2008).

    PubMed  Google Scholar 

  112. Vercellino, M. et al. Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. J. Neuropathol. Exp. Neurol. 66, 732–739 (2007).

    CAS  PubMed  Google Scholar 

  113. Hardin-Pouzet, H. et al. Glutamate metabolism is down-regulated in astrocytes during experimental allergic encephalomyelitis. Glia 20, 79–85 (1997).

    CAS  PubMed  Google Scholar 

  114. Ohgoh, M. et al. Altered expression of glutamate transporters in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 125, 170–178 (2002).

    CAS  PubMed  Google Scholar 

  115. Pitt, D., Werner, P. & Raine, C. S. Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6, 67–70 (2000).

    CAS  PubMed  Google Scholar 

  116. Smith, T., Groom, A., Zhu, B. & Turski, L. Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat. Med. 6, 62–66 (2000).

    CAS  PubMed  Google Scholar 

  117. Kanwar, J. R., Kanwar, R. K. & Krissansen, G. W. Simultaneous neuroprotection and blockade of inflammation reverses autoimmune encephalomyelitis. Brain 127, 1313–1331 (2004).

    PubMed  Google Scholar 

  118. Paul, C. & Bolton, C. Modulation of blood–brain barrier dysfunction and neurological deficits during acute experimental allergic encephalomyelitis by the N-methyl-D-aspartate receptor antagonist memantine. J. Pharmacol. Exp. Ther. 302, 50–57 (2002).

    CAS  PubMed  Google Scholar 

  119. Wallstrom, E. et al. Memantine abrogates neurological deficits, but not CNS inflammation, in Lewis rat experimental autoimmune encephalomyelitis. J. Neurol. Sci. 137, 89–96 (1996).

    CAS  PubMed  Google Scholar 

  120. Centonze, D. et al. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J. Neurosci. 29, 3442–3452 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Basso, A. S. et al. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J. Clin. Invest. 118, 1532–1543 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Wemmie, J. A., Taugher, R. J. & Kreple, C. J. Acid-sensing ion channels in pain and disease. Nat. Rev. Neurosci. 14, 461–471 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Yermolaieva, O., Leonard, A. S., Schnizler, M. K., Abboud, F. M. & Welsh, M. J. Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc. Natl Acad. Sci. USA 101, 6752–6757 (2004).

    CAS  PubMed  Google Scholar 

  124. Vergo, S. et al. Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. Brain 134, 571–584 (2011).

    PubMed  Google Scholar 

  125. Arun, T. et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain 136, 106–115 (2013).

    PubMed  Google Scholar 

  126. Hassen, G. W., Feliberti, J., Kesner, L., Stracher, A. & Mokhtarian, F. Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis. Brain Res. 1236, 206–215 (2008).

    PubMed  PubMed Central  Google Scholar 

  127. Shields, D. C., Tyor, W. R., Deibler, G. E., Hogan, E. L. & Banik, N. L. Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis. Proc. Natl Acad. Sci. USA 95, 5768–5772 (1998).

    CAS  PubMed  Google Scholar 

  128. Guyton, M. K. et al. Upregulation of calpain correlates with increased neurodegeneration in acute experimental auto-immune encephalomyelitis. J. Neurosci. Res. 81, 53–61 (2005).

    CAS  PubMed  Google Scholar 

  129. Offen, D. et al. Mice overexpressing Bcl-2 in their neurons are resistant to myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). J. Mol. Neurosci. 15, 167–176 (2000).

    CAS  PubMed  Google Scholar 

  130. Aktas, O. et al. Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 46, 421–432 (2005).

    CAS  PubMed  Google Scholar 

  131. Chitnis, T. et al. Elevated neuronal expression of CD200 protects Wlds mice from inflammation-mediated neurodegeneration. Am. J. Pathol. 170, 1695–1712 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Saxena, S. & Caroni, P. Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron 71, 35–48 (2011).

    CAS  PubMed  Google Scholar 

  133. Kemp, J. A. & McKernan, R. M. NMDA receptor pathways as drug targets. Nat. Neurosci. 5 (Suppl.), 1039–1042 (2002).

    CAS  PubMed  Google Scholar 

  134. Stranahan, A. M. & Mattson, M. P. Recruiting adaptive cellular stress responses for successful brain ageing. Nat. Rev. Neurosci. 13, 209–216 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Prakash, R. S., Snook, E. M., Motl, R. W. & Kramer, A. F. Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis. Brain Res. 1341, 41–51 (2010).

    CAS  PubMed  Google Scholar 

  136. Briken, S. et al. Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial. Mult. Scler. http://dx.doi.org/10.1177/1352458513507358.

  137. Rossi, S. et al. Exercise attenuates the clinical, synaptic and dendritic abnormalities of experimental autoimmune encephalomyelitis. Neurobiol. Dis. 36, 51–59 (2009).

    CAS  PubMed  Google Scholar 

  138. Safdar, A. et al. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc. Natl Acad. Sci. USA 108, 4135–4140 (2011).

    CAS  PubMed  Google Scholar 

  139. Maresz, K. et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat. Med. 13, 492–497 (2007).

    CAS  PubMed  Google Scholar 

  140. Kaneko, S. et al. Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models. J. Neurosci. 26, 9794–9804 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Dutta, R. et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann. Neurol. 59, 478–489 (2006).

    CAS  PubMed  Google Scholar 

  142. Campbell, G. R. et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann. Neurol. 69, 481–492 (2011).

    CAS  PubMed  Google Scholar 

  143. Mahad, D., Ziabreva, I., Lassmann, H. & Turnbull, D. Mitochondrial defects in acute multiple sclerosis lesions. Brain 131, 1722–1735 (2008).

    PubMed  PubMed Central  Google Scholar 

  144. Zambonin, J. L. et al. Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Brain 134, 1901–1913 (2011).

    PubMed  PubMed Central  Google Scholar 

  145. Linker, R. A. et al. CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nat. Med. 8, 620–624 (2002).

    CAS  PubMed  Google Scholar 

  146. Linker, R. A. et al. Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis. Brain 133, 2248–2263 (2010).

    PubMed  Google Scholar 

  147. Lu, B., Nagappan, G., Guan, X., Nathan, P. J. & Wren, P. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat. Rev. Neurosci. 14, 401–416 (2013).

    CAS  PubMed  Google Scholar 

  148. Petryshen, T. L. et al. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol. Psychiatry 15, 810–815 (2010).

    CAS  PubMed  Google Scholar 

  149. Zivadinov, R. et al. Preservation of gray matter volume in multiple sclerosis patients with the Met allele of the rs6265 (Val66Met) SNP of brain-derived neurotrophic factor. Hum. Mol. Genet. 16, 2659–2668 (2007).

    CAS  PubMed  Google Scholar 

  150. Ramasamy, D. P. et al. Effect of Met66 allele of the BDNF rs6265 SNP on regional gray matter volumes in patients with multiple sclerosis: a voxel-based morphometry study. Pathophysiology 18, 53–60 (2011).

    CAS  PubMed  Google Scholar 

  151. Nagahara, A. H. & Tuszynski, M. H. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat. Rev. Drug Discov. 10, 209–219 (2011).

    CAS  PubMed  Google Scholar 

  152. Stadelmann, C. et al. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 125, 75–85 (2002).

    PubMed  Google Scholar 

  153. Kerschensteiner, M. et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J. Exp. Med. 189, 865–870 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Lee, D. H. et al. Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination. Acta Neuropathol. 123, 247–258 (2012).

    CAS  PubMed  Google Scholar 

  155. Colombo, E. et al. Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration. J. Exp. Med. 209, 521–535 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Jones, J. L. et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 133, 2232–2247 (2010).

    PubMed  Google Scholar 

  157. Thone, J. et al. Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am. J. Pathol. 180, 267–274 (2012).

    PubMed  Google Scholar 

  158. Marsicano, G. et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84–88 (2003).

    CAS  PubMed  Google Scholar 

  159. Pryce, G. et al. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126, 2191–2202 (2003).

    PubMed  Google Scholar 

  160. Rossi, S. et al. Cannabinoid CB1 receptors regulate neuronal TNF-α effects in experimental autoimmune encephalomyelitis. Brain Behav. Immun. 25, 1242–1248 (2011).

    CAS  PubMed  Google Scholar 

  161. Croxford, J. L. et al. Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis. J. Neuroimmunol. 193, 120–129 (2008).

    CAS  PubMed  Google Scholar 

  162. Zajicek, J. et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol. 12, 857–865 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Broxmeyer, H. E. Erythropoietin: multiple targets, actions, and modifying influences for biological and clinical consideration. J. Exp. Med. 210, 205–208 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Li, W. et al. Beneficial effect of erythropoietin on experimental allergic encephalomyelitis. Ann. Neurol. 56, 767–777 (2004).

    CAS  PubMed  Google Scholar 

  165. Suhs, K. W. et al. A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis. Ann. Neurol. 72, 199–210 (2012).

    PubMed  Google Scholar 

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Acknowledgements

M.A.F. is supported by the Deutsche Forschungsgemeinschaft Emmy Noether-Programme (FR1720/3-1), Gemeinnützige Hertie-Stiftung (1.01.1/11/003 and P1130075), Werner Otto Stiftung (1/81), Forschungs- und Wissenschaftsstiftung Hamburg, Boehringer Ingelheim Stiftung Exploration Grant and BMBF Biopharma (NEU2 programme). L.F. is supported by the Wellcome Trust, the Medical Research Council, the Lundbeck Foundation and the Naomi Bransom Foundation.

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Authors and Affiliations

  1. Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, Hamburg, D-20251, Germany

    Manuel A. Friese & Benjamin Schattling

  2. Nuffield Department of Clinical Neurosciences and Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK

    Lars Fugger

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  1. Manuel A. Friese
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M.A.F. researched most of the data and drafted the article with substantial contributions from B.S. and L.F. All authors contributed to discussion of the content, reviewing, and editing of the manuscript before submission.

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Correspondence to Manuel A. Friese.

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Supplementary Table 1

Pharmacological ion channel modulation in EAE (DOC 101 kb)

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Friese, M., Schattling, B. & Fugger, L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 10, 225–238 (2014). https://doi.org/10.1038/nrneurol.2014.37

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