Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Neuroprotection and repair in multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease that is considered by many people to have an autoimmune aetiology. In recent years, new data emerging from histopathology, imaging and other studies have expanded our understanding of the disease and may change the way in which it is treated. Conceptual shifts have included: first, an appreciation of the extent to which the neuron and its axon are affected in MS, and second, elucidation of how the neurobiology of axon–glial and, particularly, axon–myelin interaction may influence disease progression. In this article, we review advances in both areas, focusing on the molecular mechanisms underlying axonal loss in acute inflammation and in chronic demyelination, and discussing how the restoration of myelin sheaths via the regenerative process of remyelination might prevent axon degeneration. An understanding of these processes could lead to better strategies for the prevention and treatment of axonal loss, which will ultimately benefit patients with MS.

Key Points

  • Axonal damage—now a recognized pathological feature of multiple sclerosis—is most severe in new inflammatory demyelinating lesions, and occurs at a slower rate during progressive disease

  • Multiple mechanisms contribute to acute axonal injury in new inflammatory lesions, including oxidative damage, energy deprivation and sodium accumulation, all of which are amenable to therapy

  • In chronic lesions, loss of the trophic support that is normally provided by intact myelinating oligodendrocytes may contribute to axonal damage

  • Remyelination represents a powerful means of preventing axonal damage attributable to loss of myelin trophic support

  • In recent years we have witnessed the emergence of an increasing number of therapeutic targets to enhance remyelination by endogenous progenitor cells, thereby reducing chronic axonal loss

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sodium-channel blockade as a neuroprotective therapy in MS.
Figure 2: Effects of sodium-channel blockade on microglia and macrophages.
Figure 3: Effects of myelin deficiency on axonal integrity.
Figure 4: Enhancement of OPC differentiation accelerates remyelination in a lysolecithin-induced model of demyelination.
Figure 5: Possible mechanisms of axonal protection and repair.

References

  1. Dutta, R. & Trapp, B. D. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog. Neurobiol. 93, 1–12 (2011).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  3. Lassmann, H. New concepts on progressive multiple sclerosis. Curr. Neurol. Neurosci. Rep. 7, 239–244 (2007).

    Article  PubMed  Google Scholar 

  4. Trapp, B. et al. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Bjartmar, C. & Trapp, B. D. Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr. Opin. Neurol. 14, 271–278 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Medana, I., Martinic, M. A., Wekerle, H. & Neumann, H. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am. J. Pathol. 159, 809–815 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Barnett, M. H. & Prineas, J. W. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann. Neurol. 55, 458–468 (2004).

    Article  PubMed  Google Scholar 

  8. Marik, C., Felts, P. A., Bauer, J., Lassmann, H. & Smith, K. J. Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130, 2800–2815 (2007).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mahad, D., Lassmann, H. & Turnbull, D. Review: mitochondria and disease progression in multiple sclerosis. Neuropathol. Appl. Neurobiol. 34, 577–589 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Aboul-Enein, F. & Lassmann, H. Mitochondrial damage and histotoxic hypoxia: a pathway of tissue injury in inflammatory brain disease? Acta Neuropathol. 109, 49–55 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Bechtold, D. A. & Smith, K. J. Sodium-mediated axonal degeneration in inflammatory demyelinating disease. J. Neurol. Sci. 233, 27–35 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. Murphy, M. P. Mitochondria—a neglected drug target. Curr. Opin. Investig. Drugs 10, 1022–1024 (2009).

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  20. Smith, K. J. Newly lesioned tissue in multiple sclerosis—a role for oxidative damage? Brain 134, 1877–1881 (2011).

    Article  PubMed  Google Scholar 

  21. Wheaton, W. W. & Chandel, N. S. Hypoxia. 2. Hypoxia regulates cellular metabolism. Am. J. Physiol. Cell Physiol. 300, C385–C393 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Qi, X., Sun, L., Lewin, A. S., Hauswirth, W. W. & Guy, J. Long-term suppression of neurodegeneration in chronic experimental optic neuritis: antioxidant gene therapy. Invest. Ophthalmol. Vis. Sci. 48, 5360–5370 (2007).

    Article  PubMed  Google Scholar 

  24. Cocheme, H. M. & Murphy, M. P. Can antioxidants be effective therapeutics? Curr. Opin. Investig. Drugs 11, 426–431 (2010).

    CAS  PubMed  Google Scholar 

  25. Murphy, M. P. & Smith, R. A. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu. Rev. Pharmacol. Toxicol. 47, 629–656 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Ascherio, A., Munger, K. L. & Lünemann, J. D. The initiation and prevention of multiple sclerosis. Nat. Rev. Neurol. http://dx.doi.org/10.1038/nrneurol.2012.198

  27. van Horssen, J., Witte, M. E., Schreibelt, G. & de Vries, H. E. Radical changes in multiple sclerosis pathogenesis. Biochim. Biophys. Acta 1812, 141–150 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Aguirre, E., Rodriguez-Juarez, F., Bellelli, A., Gnaiger, E. & Cadenas, S. Kinetic model of the inhibition of respiration by endogenous nitric oxide in intact cells. Biochim. Biophys. Acta 1797, 557–565 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Smith, K. J. & McDonald, W. I. Spontaneous and mechanically evoked activity due to central demyelinating lesion. Nature 286, 154–155 (1980).

    Article  CAS  PubMed  Google Scholar 

  31. Kapoor, R., Li, Y. G. & Smith, K. J. Slow sodium-dependent potential oscillations contribute to ectopic firing in mammalian demyelinated axons. Brain 120, 647–652 (1997).

    Article  PubMed  Google Scholar 

  32. Iwata, A. et al. Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors. J. Neurosci. 24, 4605–4613 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cummins, T. R., Dib-Hajj, S. D., Herzog, R. I. & Waxman, S. G. Nav1.6 channels generate resurgent sodium currents in spinal sensory neurons. FEBS Lett. 579, 2166–2170 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Stys, P. K., Ransom, B. R. & Waxman, S. G. Tertiary and quaternary local anesthetics protect CNS white matter from anoxic injury at concentrations that do not block excitability. J. Neurophysiol. 67, 236–240 (1992).

    Article  CAS  PubMed  Google Scholar 

  35. Fern, R., Ransom, B. R., Stys, P. K. & Waxman, S. G. Pharmacological protection of CNS white matter during anoxia: actions of phenytoin, carbamazepine and diazepam. J. Pharmacol. Exp. Ther. 266, 1549–1555 (1993).

    CAS  PubMed  Google Scholar 

  36. Kapoor, R., Davies, M., Blaker, P. A., Hall, S. M. & Smith, K. J. Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann. Neurol. 53, 174–180 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Garthwaite, G., Goodwin, D. A., Batchelor, A. M., Leeming, K. & Garthwaite, J. Nitric oxide toxicity in CNS white matter: an in vitro study using rat optic nerve. Neuroscience 109, 145–155 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Lo, A. C., Black, J. A. & Waxman, S. G. Neuroprotection of axons with phenytoin in experimental allergic encephalomyelitis. Neuroreport 13, 1909–1912 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  Google Scholar 

  43. Black, J. A. & Waxman, S. G. Sodium channels and microglial function. Exp. Neurol. 234, 302–315 (2011).

    Article  PubMed  CAS  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  46. US National Library of Medicine. Neuroprotection with phenytoin in optic neuritis. ClinicalTrials.gov [online], (2011).

  47. Trapp, B. D. & Nave, K. A. Multiple sclerosis: an immune or neurodegenerative disorder? Ann. Rev. Neurosci. 31, 247–269 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Griffiths, I. et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610–1613 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Pan, B. et al. Myelin-associated glycoprotein and complementary axonal ligands, gangliosides, mediate axon stability in the CNS and PNS: neuropathology and behavioral deficits in single- and double-null mice. Exp. Neurol. 195, 208–217 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yin, X. et al. Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J. Neurosci. 18, 1953–1962 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lappe-Siefke, C. et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat. Genet. 33, 366–374 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Boison, D. & Stoffel, W. Disruption of the compacted myelin sheath of axons of the central nervous system in proteolipid protein-deficient mice. Proc. Natl Acad. Sci. USA 91, 11709–11713 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Klugmann, M. et al. Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18, 59–70 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Edgar, J. M. et al. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J. Cell Biol. 166, 121–131 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Garbern, J. Y. 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 125, 551–561 (2002).

    Article  PubMed  Google Scholar 

  56. Yin, X. et al. Evolution of a neuroprotective function of central nervous system myelin. J. Cell Biol. 172, 469–478 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Edgar, J. M. & Nave, K. A. The role of CNS glia in preserving axon function. Curr. Opin. Neurobiol. 19, 498–504 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Braun, P. E., Sandillon, F., Edwards, A., Matthieu, J. M. & Privat, A. Immunocytochemical localization by electron microscopy of 2′,3′-cyclic nucleotide 3′-phosphodiesterase in developing oligodendrocytes of normal and mutant brain. J. Neurosci. 8, 3057–3066 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Trapp, B. D., Bernier, L., Andrews, S. B. & Colman, D. R. Cellular and subcellular distribution of 2′,3′-cyclic nucleotide 3′-phosphodiesterase and its mRNA in the rat central nervous system. J. Neurochem. 51, 859–868 (1988).

    Article  CAS  PubMed  Google Scholar 

  60. Trapp, B. D., Andrews, S. B., Cootauco, C. & Quarles, R. The myelin-associated glycoprotein is enriched in multivesicular bodies and periaxonal membranes of actively myelinating oligodendrocytes. J. Cell Biol. 109, 2417–2426 (1989).

    Article  CAS  PubMed  Google Scholar 

  61. Li, C. et al. Myelination in the absense of myelin-associated glycoprotein. Nature 369, 747–750 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Montag, D. et al. Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 13, 229–246 (1994).

    Article  CAS  PubMed  Google Scholar 

  63. Fruttiger, M., Montag, D., Schachner, M. & Martini, R. Crucial role for the myelin-associated glycoprotein in the maintenance of axon-myelin integrity. Eur. J. Neurosci. 7, 511–515 (1995).

    Article  CAS  PubMed  Google Scholar 

  64. Weiss, M. D., Luciano, C. A. & Quarles, R. H. Nerve conduction abnormalities in aging mice deficient for myelin-associated glycoprotein. Muscle Nerve 24, 1380–1387 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Nguyen, T. et al. Axonal protective effects of the myelin-associated glycoprotein. J. Neurosci. 29, 630–637 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pohl, H. B. et al. Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage. J. Neurosci. 31, 1069–1080 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Spencer, P. S. & Thomas, P. K. Ultrastructural studies of the dying-back process. II. The sequestration and removal by Schwann cells and oligodendrocytes of organelles from normal and diseases axons. J. Neurocytol. 3, 763–783 (1974).

    Article  CAS  PubMed  Google Scholar 

  68. Novotny, G. E. Formation of cytoplasm-containing vesicles from double-walled coated invaginations containing oligodendrocytic cytoplasm at the axon-myelin sheath interface in adult mammalian central nervous system. Acta Anat. (Basel) 119, 106–112 (1984).

    Article  CAS  Google Scholar 

  69. Kramer-Albers, E. M. et al. Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: trophic support for axons? Proteomics Clin. Appl. 1, 1446–1461 (2007).

    Article  PubMed  CAS  Google Scholar 

  70. Wilkins, A., Majed, H., Layfield, R., Compston, A. & Chandran, S. 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. 23, 4967–4974 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Morfini, G. A. et al. Axonal transport defects in neurodegenerative diseases. J. Neurosci. 29, 12776–12786 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Xu, M., Gu, Y., Barry, J. & Gu, C. Kinesin I transports tetramerized Kv3 channels through the axon initial segment via direct binding. J. Neurosci. 30, 15987–1 6001.

    Article  CAS  Google Scholar 

  73. Zhang, Y. et al. Assembly and maintenance of nodes of Ranvier rely on distinct sources of proteins and targeting mechanisms. Neuron 73, 92–107 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mutsaers, S. E. & Carroll, W. M. Focal accumulation of intra-axonal mitochondria in demyelination of the cat optic nerve. Acta Neuropathol. 96, 139–143 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Kiryu-Seo, S., Ohno, N., Kidd, G. J., Komuro, H. & Trapp, B. D. Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. J. Neurosci. 30, 6658–6666 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Witt, A. & Brady, S. T. Unwrapping new layers of complexity in axon/glial relationships. Glia 29, 112–117 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Adalbert, R. et al. Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies. Brain 132, 402–416 (2009).

    Article  PubMed  Google Scholar 

  78. Marinkovic, P. et al. Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 109, 4296–4301 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nave, K. A. Myelination and the trophic support of long axons. Nat. Rev. Neurosci. 11, 275–283 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Stys, P. K. The axo–myelinic synapse. Trends Neurosci. 34, 393–400 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Dale, J. M. & Garcia, M. L. Neurofilament phosphorylation during development and disease: which came first, the phosphorylation or the accumulation? J. Amino Acids 2012, 382107 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Dashiell, S. M., Tanner, S. L., Pant, H. C. & Quarles, R. H. Myelin-associated glycoprotein modulates expression and phosphorylation of neuronal cytoskeletal elements and their associated kinases. J. Neurochem. 81, 1263–1272 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Franzen, R. et al. Microtubule-associated protein 1B: a neuronal binding partner for myelin-associated glycoprotein. J. Cell Biol. 155, 893–898 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kassmann, C. M. et al. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat. Genet. 39, 969–976 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Dhaunchak, A. S. et al. Implication of perturbed axoglial apparatus in early pediatric multiple sclerosis. Ann. Neurol. 71, 601–613 (2012).

    Article  PubMed  Google Scholar 

  88. Franklin, R. J. M. Why does remyelination fail in multiple sclerosis? Nat. Rev. Neurosci. 3, 705–714 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Patani, R., Balaratnam, M., Vora, A. & Reynolds, R. Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathol. Appl. Neurobiol. 33, 277–287 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Patrikios, P. et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129, 3165–3172 (2006).

    Article  PubMed  Google Scholar 

  91. Franklin, R. J. M. & ffrench-Constant, C. Remyelination in the CNS: from biology to therapy. Nat. Rev. Neurosci. 9, 839–855 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Zawadzka, M. et al. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell 6, 578–590 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Nait-Oumesmar, B., Picard-Riera, N., Kerninon, C. & Baron-Van Evercooren, A. The role of SVZ-derived neural precursors in demyelinating diseases: from animal models to multiple sclerosis. J. Neurol. Sci. 265, 26–31 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Menn, B. et al. Origin of oligodendrocytes in the subventricular zone of the adult brain. J. Neurosci. 26, 7907–7918 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Smith, K. J., Blakemore, W. F. & McDonald, W. I. Central remyelination restores secure conduction. Nature 280, 395–396 (1979).

    Article  CAS  PubMed  Google Scholar 

  96. Jeffery, N. D. & Blakemore, W. F. Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. Brain 120, 27–37 (1997).

    Article  PubMed  Google Scholar 

  97. Duncan, I. D., Brower, A., Kondo, Y., Curlee, J. F. Jr & Schultz, R. D. Extensive remyelination of the CNS leads to functional recovery. Proc. Natl Acad. Sci. USA 106, 6832–6836 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Smith, K. J. Axonal protection in multiple sclerosis—a particular need during remyelination? Brain 129, 3147–3149 (2006).

    Article  PubMed  Google Scholar 

  99. Coman, I. et al. Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain 129, 3186–3195 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Prineas, J. W. & Connell, F. Remyelination in multiple sclerosis. Ann. Neurol. 5, 22–31 (1979).

    Article  CAS  PubMed  Google Scholar 

  101. Howell, O. W. et al. Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain 129, 3173–3185 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Kuhlmann, T., Lingfeld, G., Bitsch, A., Schuchardt, J. & Bruck, W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125, 2202–2212 (2002).

    Article  PubMed  Google Scholar 

  103. Rist, J. M. & Franklin, R. J. M. Taking ageing into account in remyelination-based therapies for multiple sclerosis. J. Neurol. Sci. 274, 64–67 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Goldschmidt, T., Antel, J., Konig, F. B., Bruck, W. & Kuhlmann, T. Remyelination capacity of the MS brain decreases with disease chronicity. Neurology 72, 1914–1921 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Confavreux, C. & Vukusic, S. Age at disability milestones in multiple sclerosis. Brain 129, 595–605 (2006).

    Article  PubMed  Google Scholar 

  106. Irvine, K. A. & Blakemore, W. F. Age increases axon loss associated with primary demyelination in cuprizone-induced demyelination in C57BL/6 mice. J. Neuroimmunol. 175, 69–76 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Woodruff, R. H., Fruttiger, M., Richardson, W. D. & Franklin, R. J. M. Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination. Mol. Cell. Neurosci. 25, 252–262 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Shen, S. et al. Age-dependent epigenetic control of differentiation inhibitors: a critical determinant of remyelination efficiency. Nat. Neurosci. 11, 1024–1034 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wolswijk, G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J. Neurosci. 18, 601–609 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Chang, A., Tourtellotte, W. W., Rudick, R. & Trapp, B. D. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N. Engl. J. Med. 346, 165–173 (2002).

    Article  PubMed  Google Scholar 

  111. Ruckh, J. M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Fancy, S. P. et al. Overcoming remyelination failure in multiple sclerosis and other myelin disorders. Exp. Neurol. 225, 18–23 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Huang, J. K. et al. Myelin regeneration in multiple sclerosis: targeting endogenous stem cells. Neurotherapeutics 8, 650–658 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Piaton, G. et al. Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system. Brain 134, 1156–1167 (2011).

    Article  PubMed  Google Scholar 

  115. Kotter, M. R., Stadelmann, C. & Hartung, H. P. Enhancing remyelination in disease—can we wrap it up? Brain 134, 1882–1900 (2011).

    Article  PubMed  Google Scholar 

  116. Mi, S. et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat. Neurosci. 8, 745–751 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Mi, S. et al. Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells. Ann. Neurol. 65, 304–315 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Rudick, R. A., Mi, S. & Sandrock, A. W. Jr. LINGO-1 antagonists as therapy for multiple sclerosis: in vitro and in vivo evidence. Expert Opin. Biol. Ther. 8, 1561–1570 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Fancy, S. P. et al. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev. 23, 1571–1585 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fancy, S. P. et al. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nat. Neurosci. 14, 1009–1016 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Huang, J. K. et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat. Neurosci. 14, 45–53 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Ballanger, F., Nguyen, J. M., Khammari, A. & Dreno, B. Evolution of clinical and molecular responses to bexarotene treatment in cutaneous T-cell lymphoma. Dermatology 220, 370–375 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Diab, A. et al. Ligands for the peroxisome proliferator-activated receptor-γ and the retinoid X receptor exert additive anti-inflammatory effects on experimental autoimmune encephalomyelitis. J. Neuroimmunol. 148, 116–126 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Xu, J. & Drew, P. D. 9-Cis-retinoic acid suppresses inflammatory responses of microglia and astrocytes. J. Neuroimmunol. 171, 135–144 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Cramer, P. E. et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kotter, M. R., Li, W. W., Zhao, C. & Franklin, R. J. M. Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J. Neurosci. 26, 328–332 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lucchinetti, C. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47, 707–717 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to researching of data for the article, discussion of content, writing, and review and editing of the manuscript before submission.

Corresponding author

Correspondence to Robin J. M. Franklin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Franklin, R., ffrench-Constant, C., Edgar, J. et al. Neuroprotection and repair in multiple sclerosis. Nat Rev Neurol 8, 624–634 (2012). https://doi.org/10.1038/nrneurol.2012.200

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2012.200

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing