Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that involves demyelination and axonal degeneration. Although substantial progress has been made in drug development for relapsing–remitting MS, treatment of the progressive forms of the disease, which are characterized clinically by the accumulation of disability in the absence of relapses, remains unsatisfactory. This unmet clinical need is related to the complexity of the pathophysiological mechanisms involved in MS progression. Chronic inflammation, which occurs behind a closed blood–brain barrier with activation of microglia and continued involvement of T cells and B cells, is a hallmark pathophysiological feature. Inflammation can enhance mitochondrial damage in neurons, which, consequently, develop an energy deficit, further reducing axonal health. The growth-inhibitory and inflammatory environment of lesions also impairs remyelination, a repair process that might protect axons from degeneration. Moreover, neurodegeneration is accelerated by the altered expression of ion channels on denuded axons. In this Review, we discuss the current understanding of these disease mechanisms and highlight emerging therapeutic strategies based on these insights, including those targeting the neuroinflammatory and degenerative aspects as well as remyelination-promoting approaches.
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References
Reich, D. S., Lucchinetti, C. F. & Calabresi, P. A. Multiple sclerosis. N. Engl. J. Med. 378, 169–180 (2018).
Weinshenker, B. G. et al. The natural history of multiple sclerosis: a geographically based study. I. clinical course and disability. Brain 112 (Pt 1), 133–146 (1989).
Torkildsen, O., Myhr, K. M. & Bo, L. Disease-modifying treatments for multiple sclerosis – a review of approved medications. Eur. J. Neurol. 23 (Suppl. 1), 18–27 (2016).
Brown, J. W. L. et al. Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis. JAMA 321, 175–187 (2019).
Lublin, F. et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 387, 1075–1084 (2016).
Montalban, X. et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N. Engl. J. Med. 376, 209–220 (2017). This pivotal trial shows the efficacy of ocrelizumab in PPMS and forms the basis of its FDA and EMA approval.
Kappos, L. et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 391, 1263–1273 (2018). This study reports that siponimod treatment led to a 21% reduced risk of disability progression in SPMS.
Plemel, J. R., Liu, W. Q. & Yong, V. W. Remyelination therapies: a new direction and challenge in multiple sclerosis. Nat. Rev. Drug Discov. 16, 617–634 (2017). A comprehensive summary of potential remyelinating medications.
Kutzelnigg, A. & Lassmann, H. Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handb. Clin. Neurol. 122, 15–58 (2014).
Frischer, J. M. et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132, 1175–1189 (2009).
Hochmeister, S. et al. Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J. Neuropathol. Exp. Neurol. 65, 855–865 (2006).
Lassmann, H. Targets of therapy in progressive MS. Mult. Scler. 23, 1593–1599 (2017).
Dal-Bianco, A. et al. Slow expansion of multiple sclerosis iron rim lesions: pathology and 7T magnetic resonance imaging. Acta Neuropathol. 133, 25–42 (2017).
Kutzelnigg, A. et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128, 2705–2712 (2005). A key neuropathology study, showing the association between cortical demyelination and white matter injury.
Androdias, G. et al. Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords. Ann Neurol 68, 465–476 (2010).
Komori, M. et al. Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis. Ann. Neurol. 78, 3–20 (2015).
Lassmann, H. Pathogenic mechanisms associated with different clinical courses of multiple sclerosis. Front. Immunol. 9, 3116 (2018).
Schenkel, J. M. & Masopust, D. Tissue-resident memory T cells. Immunity 41, 886–897 (2014).
Kapoor, R. et al. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol. 17, 405–415 (2018).
Greenwood, J., Steinman, L. & Zamvil, S. S. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat. Rev. Immunol. 6, 358–370 (2006).
de Oliveira, D. M. et al. Simvastatin ameliorates experimental autoimmune encephalomyelitis by inhibiting Th1/Th17 response and cellular infiltration. Inflammopharmacology 23, 343–354 (2015).
Zhang, X., Tao, Y., Troiani, L. & Markovic-Plese, S. Simvastatin inhibits IFN regulatory factor 4 expression and Th17 cell differentiation in CD4+T cells derived from patients with multiple sclerosis. J. Immunol. 187, 3431–3437 (2011).
Paintlia, A. S. et al. HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. FASEB J. 19, 1407–1421 (2005).
Wang, J., Xiao, Y., Luo, M. & Luo, H. Statins for multiple sclerosis. Cochrane Database Syst. Rev. 12, CD008386 (2011).
Chataway, J. et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 383, 2213–2221 (2014).
Chan, D. et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol. 16, 591–600 (2017).
Kurte, M. et al. IL17/IL17RA as a novel signaling axis driving mesenchymal stem cell therapeutic function in experimental autoimmune encephalomyelitis. Front. Immunol. 9, 802 (2018).
Rice, C. M. et al. Safety and feasibility of autologous bone marrow cellular therapy in relapsing-progressive multiple sclerosis. Clin. Pharmacol. Ther. 87, 679–685 (2010).
Connick, P. et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 11, 150–156 (2012).
Rice, C. M. et al. Assessment of bone marrow-derived cellular therapy in progressive multiple sclerosis (ACTiMuS): study protocol for a randomised controlled trial. Trials 16, 463 (2015).
Mancardi, G. L. et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology 84, 981–988 (2015).
Burt, R. K. et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial. JAMA 321, 165–174 (2019).
Muraro, P. A. et al. Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 74, 459–469 (2017). A meta-analysis of studies investigating stem cell transplantation in MS.
Michel, L. et al. B cells in the multiple sclerosis central nervous system: trafficking and contribution to CNS-compartmentalized inflammation. Front. Immunol. 6, 636 (2015).
Pollinger, B. et al. Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells. J. Exp. Med. 206, 1303–1316 (2009).
Li, R. et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci. Transl Med. 7, 310ra166 (2015).
Magliozzi, R. et al. B-cell enrichment and Epstein-Barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis. J. Neuropathol. Exp. Neurol. 72, 29–41 (2013).
Howell, O. W. et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 134, 2755–2771 (2011). A key neuropathological study, demonstrating the link between meningeal inflammation and cortical neurodegeneration.
Choi, S. R. et al. Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. Brain 135, 2925–2937 (2012).
Magliozzi, R. et al. A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann. Neurol. 68, 477–493 (2010).
Romme Christensen, J. et al. Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression. PLOS ONE 8, e57820 (2013).
Blauth, K. et al. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants. Acta Neuropathol. 130, 765–781 (2015).
Rojas, O. L. et al. Recirculating intestinal IgA-producing cells regulate neuroinflammation via IL-10. Cell 176, 610–624.e618 (2019).
Kappos, L. et al. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol. 13, 353–363 (2014).
Hawker, K. et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 66, 460–471 (2009).
Piccio, L. et al. Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis. Arch. Neurol. 67, 707–714 (2010).
Fereidan-Esfahani, M., Bruck, W. & Weber, M. S. Targeting central nervous system B cells in progression of multiple sclerosis: is intrathecal anti-CD20 a therapeutic option? JAMA Neurol. 72, 1407–1408 (2015).
Svenningsson, A. et al. Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally. Neurol. Neuroimmunol. Neuroinflamm. 2, e79 (2015).
Komori, M. et al. Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann. Clin. Transl. Neurol. 3, 166–179 (2016).
Naegelin, Y. et al. Association of rituximab treatment with disability progression among patients with secondary progressive multiple sclerosis. JAMA Neurol. 76, 274-281, (2019).
Siders, W. et al. GZ402668, a next-generation anti-CD52 antibody, displays decreased proinflammatory cytokine release in vitro. Neurology 86 (Suppl. 16), P3.068 (2016).
Lassmann, H., van Horssen, J. & Mahad, D. Progressive multiple sclerosis: pathology and pathogenesis. Nat. Rev. Neurol. 8, 647–656 (2012). A key review on the neuropathology of progressive MS.
Nikic, I. et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med. 17, 495–499 (2011).
Radbruch, H. et al. Ongoing oxidative stress causes subclinical neuronal dysfunction in the recovery phase of EAE. Front. Immunol. 7, 92 (2016).
Sawada, H. et al. Activated microglia affect the nigro-striatal dopamine neurons differently in neonatal and aged mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J. Neurosci. Res. 85, 1752–1761 (2007).
Streit, W. J. & Xue, Q. S. Human CNS immune senescence and neurodegeneration. Curr. Opin. Immunol. 29, 93–96 (2014).
Ransohoff, R. M. A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987–991 (2016).
Herder, V. et al. Dynamic changes of microglia/macrophage M1 and M2 polarization in Theiler’s murine encephalomyelitis. Brain Pathol. 25, 712–723 (2015).
Miron, V. E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013). This study shows the role of M2 myeloid cells in supporting oligodendrocyte differentiation.
Koch, M. W. et al. Hydroxychloroquine reduces microglial activity and attenuates experimental autoimmune encephalomyelitis. J. Neurol. Sci. 358, 131–137 (2015).
White, M., Webster, G., O’Sullivan, D., Stone, S. & La Flamme, A. C. Targeting innate receptors with MIS416 reshapes Th responses and suppresses CNS disease in a mouse model of multiple sclerosis. PLOS ONE 9, e87712 (2014).
Cho, Y. et al. Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc. Natl Acad. Sci. USA 107, 11313–11318 (2010).
Fox, R. J. et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp. Clin. Trials 50, 166–177 (2016).
Fox, R. J. et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. N. Engl. J. Med. 379, 846–855 (2018). This trial showed reduced brain atrophy in progressive MS upon ibudilast treatment.
Chechneva, O. V. et al. Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord. Neurobiol. Dis. 44, 63–72 (2011).
Lisak, R. P., Nedelkoska, L. & Benjamins, J. A. Effects of dextromethorphan on glial cell function: proliferation, maturation, and protection from cytotoxic molecules. Glia 62, 751–762 (2014).
Liu, Y. et al. Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J. Pharmacol. Exp. Ther. 305, 212–218 (2003).
Spain, R. et al. Lipoic acid in secondary progressive MS: a randomized controlled pilot trial. Neurol. Neuroimmunol. Neuroinflamm. 4, e374 (2017).
Faissner, S. & Gold, R. Efficacy and safety of the newer multiple sclerosis drugs approved since 2010. CNS Drugs 32, 269–287 (2018).
Faissner, S. & Gold, R. Oral therapies for multiple sclerosis. Cold Spring Harb. Perspect. Med. 9, a032011 (2019).
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).
Strassburger-Krogias, K. et al. Fumarate treatment in progressive forms of multiple sclerosis: first results of a single-center observational study. Ther. Adv. Neurol. Disord. 7, 232–238 (2014).
Valentin-Torres, A. et al. Sustained TNF production by central nervous system infiltrating macrophages promotes progressive autoimmune encephalomyelitis. J. Neuroinflammation 13, 46 (2016).
Theibich, A., Dreyer, L., Magyari, M. & Locht, H. Demyelinizing neurological disease after treatment with tumor necrosis factor alpha-inhibiting agents in a rheumatological outpatient clinic: description of six cases. Clin. Rheumatol. 33, 719–723 (2014).
The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53, 457–465 (1999).
Steelman, A. J. & Li, J. Astrocyte galectin-9 potentiates microglial TNF secretion. J. Neuroinflammation 11, 144 (2014).
Burman, J. & Svenningsson, A. Cerebrospinal fluid concentration of galectin-9 is increased in secondary progressive multiple sclerosis. J. Neuroimmunol. 292, 40–44 (2016).
Savarin, C. et al. Astrocyte response to IFN-gamma limits IL-6-mediated microglia activation and progressive autoimmune encephalomyelitis. J. Neuroinflammation 12, 79 (2015).
Araki, M. et al. Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab. Mod. Rheumatol. 23, 827–831 (2013).
Araki, M. et al. Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology 82, 1302–1306 (2014).
Sato, H. et al. Tocilizumab treatment safety in rheumatoid arthritis in a patient with multiple sclerosis: a case report. BMC Res. Notes 7, 641 (2014).
Beauchemin, P. & Carruthers, R. MS arising during tocilizumab therapy for rheumatoid arthritis. Mult. Scler. 22, 254–256 (2016).
Brundula, V., Rewcastle, N. B., Metz, L. M., Bernard, C. C. & Yong, V. W. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 125, 1297–1308 (2002).
Giuliani, F., Hader, W. & Yong, V. W. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. J. Leuk. Biol. 78, 135–143 (2005).
Giuliani, F., Fu, S. A., Metz, L. M. & Yong, V. W. Effective combination of minocycline and interferon-beta in a model of multiple sclerosis. J. Neuroimmunol. 165, 83–91 (2005).
Giuliani, F. et al. Additive effect of the combination of glatiramer acetate and minocycline in a model of MS. J. Neuroimmunol. 158, 213–221 (2005).
Metz, L. M. et al. Glatiramer acetate in combination with minocycline in patients with relapsing–remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial. Mult. Scler. 15, 1183–1194 (2009).
Metz, L. M. et al. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N. Engl. J. Med. 376, 2122–2133 (2017).
Sorensen, P. S. et al. Minocycline added to subcutaneous interferon beta-1a in multiple sclerosis: randomized RECYCLINE study. Eur. J. Neurol. 23, 861–870 (2016).
Yi, W., Schluter, D. & Wang, X. Astrocytes in multiple sclerosis and experimental autoimmune encephalomyelitis: Star-shaped cells illuminating the darkness of CNS autoimmunity. Brain Behav. Immun. https://doi.org/10.1016/j.bbi.2019.05.029 (2019).
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
Rothhammer, V. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018).
Mayo, L. et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat. Med. 20, 1147–1156 (2014).
Pebay, A. et al. Sphingosine-1-phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades. Eur. J. Neurosci. 13, 2067–2076 (2001).
Bigaud, M., Guerini, D., Billich, A., Bassilana, F. & Brinkmann, V. Second generation S1P pathway modulators: research strategies and clinical developments. Biochim. Biophys. Acta 1841, 745–758 (2014).
Rouach, N. et al. S1P inhibits gap junctions in astrocytes: involvement of G and Rho GTPase/ROCK. Eur. J. Neurosci. 23, 1453–1464 (2006).
Choi, J. W. et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc. Natl Acad. Sci. USA 108, 751–756 (2011).
Stephenson, E., Nathoo, N., Mahjoub, Y., Dunn, J. F. & Yong, V. W. Iron in multiple sclerosis: roles in neurodegeneration and repair. Nat. Rev. Neurol. 10, 459–468 (2014).
Haider, L. et al. Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron. J. Neurol. Neurosurg. Psychiatry 85, 1386–1395 (2014).
Friese, M. A., Schattling, B. & Fugger, L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat. Rev. Neurol. 10, 225–238 (2014).
Hametner, S. et al. Iron and neurodegeneration in the multiple sclerosis brain. Ann. Neurol. 74, 848–861 (2013).
Kroner, A. et al. TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 83, 1098–1116 (2014).
Zarruk, J. G. et al. Expression of iron homeostasis proteins in the spinal cord in experimental autoimmune encephalomyelitis and their implications for iron accumulation. Neurobiol. Dis. 81, 93–107 (2015).
Faissner, S. et al. Unexpected additive effects of minocycline and hydroxychloroquine in models of multiple sclerosis: prospective combination treatment for progressive disease? Mult. Scler. 24, 1543–1556 (2017).
Weigel, K. J., Lynch, S. G. & LeVine, S. M. Iron chelation and multiple sclerosis. ASN Neuro. 6, e00136 (2014).
Lynch, S. G., Peters, K. & LeVine, S. M. Desferrioxamine in chronic progressive multiple sclerosis: a pilot study. Mult. Scler. 2, 157–160 (1996).
Lynch, S. G., Fonseca, T. & LeVine, S. M. A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell. Mol. Biol. 46, 865–869 (2000).
Faissner, S. et al. Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic. Nat. Commun. 8, 1990 (2017). This systematic screening of generic medications identified several medications that are protective against iron-mediated neurotoxicity.
Mahad, D., Ziabreva, I., Lassmann, H. & Turnbull, D. Mitochondrial defects in acute multiple sclerosis lesions. Brain 131, 1722–1735 (2008). This study investigated mitochondrial defects in MS.
Witte, M. E. et al. Enhanced number and activity of mitochondria in multiple sclerosis lesions. J. Pathol. 219, 193–204 (2009).
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).
Zambonin, J. L. et al. Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Brain 134, 1901–1913 (2011).
Campbell, G. R. et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann. Neurol. 69, 481–492 (2011).
Campbell, G. R. et al. Clonally expanded mitochondrial DNA deletions within the choroid plexus in multiple sclerosis. Acta Neuropathol. 124, 209–220 (2012).
Tranah, G. J. et al. Mitochondrial DNA sequence variation in multiple sclerosis. Neurology 85, 325–330 (2015).
Witte, M. E., Geurts, J. J., de Vries, H. E., van der Valk, P. & van Horssen, J. Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion 10, 411–418 (2010).
Lucchinetti, C. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47, 707–717 (2000).
Mahad, D. J. et al. Mitochondrial changes within axons in multiple sclerosis. Brain 132, 1161–1174 (2009).
Haider, L. et al. Oxidative damage in multiple sclerosis lesions. Brain 134, 1914–1924 (2011).
Mitsumoto, A., Takeuchi, A., Okawa, K. & Nakagawa, Y. A subset of newly synthesized polypeptides in mitochondria from human endothelial cells exposed to hydroperoxide stress. Free Radic. Biol. Med. 32, 22–37 (2002).
Talla, V. et al. Gene therapy with mitochondrial heat shock protein 70 suppresses visual loss and optic atrophy in experimental autoimmune encephalomyelitis. Invest. Ophthalmol. Vis. Sci. 55, 5214–5226 (2014).
Trapp, B. D. et al. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998). This is the first report of the profound destruction of axons within MS lesions.
Mahad, D. H., Trapp, B. D. & Lassmann, H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 14, 183–193 (2015).
Mews, I., Bergmann, M., Bunkowski, S., Gullotta, F. & Bruck, W. Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Mult. Scler. 4, 55–62 (1998).
Bitsch, A., Schuchardt, J., Bunkowski, S., Kuhlmann, T. & Bruck, W. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123 (Pt 6), 1174–1183 (2000).
Sorbara, C. D. et al. Pervasive axonal transport deficits in multiple sclerosis models. Neuron 84, 1183–1190 (2014).
Zheng, Y. R., Zhang, X. N. & Chen, Z. Mitochondrial transport serves as a mitochondrial quality control strategy in axons: implications for central nervous system disorders. CNS Neurosci. Ther. 25, 876–886 (2019).
Joshi, D. C. et al. Deletion of mitochondrial anchoring protects dysmyelinating shiverer: implications for progressive MS. J. Neurosci. 35, 5293–5306 (2015).
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).
Waxman, S. G. Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis – current status. Nat. Clin. Pract. Neurol. 4, 159–169 (2008).
Stys, P. K., Waxman, S. G. & Ransom, B. R. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger. J. Neurosci. 12, 430–439 (1992).
Paling, D. et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain 136, 2305–2317 (2013).
Raftopoulos, R. et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 15, 259–269 (2016).
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).
Craner, M. J. et al. Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia 49, 220–229 (2005).
Miller, D. H. et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 68, 1390–1401 (2007).
Zivadinov, R. et al. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology 71, 136–144 (2008).
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). This study implicates ASIC1 as a potential therapeutic target for progressive MS.
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).
Arun, T. et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain 136, 106–115 (2013).
Hundehege, P. et al. Targeting voltage-dependent calcium channels with pregabalin exerts a direct neuroprotective effect in an animal model of multiple sclerosis. Neurosignals 26, 77–93 (2018).
Daneshdoust, D. et al. Pregabalin enhances myelin repair and attenuates glial activation in lysolecithin-induced demyelination model of rat optic chiasm. Neuroscience 344, 148–156 (2017).
Mehta, A., Prabhakar, M., Kumar, P., Deshmukh, R. & Sharma, P. L. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur. J. Pharmacol. 698, 6–18 (2013).
Tisell, A. et al. Increased concentrations of glutamate and glutamine in normal-appearing white matter of patients with multiple sclerosis and normal MR imaging brain scans. PLOS ONE 8, e61817 (2013).
MacMillan, E. L. et al. Progressive multiple sclerosis exhibits decreasing glutamate and glutamine over two years. Mult. Scler. 22, 112–116 (2016).
Pitt, D., Werner, P. & Raine, C. S. Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6, 67–70 (2000).
Wang, S. J., Wang, K. Y. & Wang, W. C. Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes). Neuroscience 125, 191–201 (2004).
Azbill, R. D., Mu, X. & Springer, J. E. Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res. 871, 175–180 (2000).
Gilgun-Sherki, Y., Panet, H., Melamed, E. & Offen, D. Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis. Brain Res. 989, 196–204 (2003).
Kalkers, N. F., Barkhof, F., Bergers, E., van Schijndel, R. & Polman, C. H. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult. Scler. 8, 532–533 (2002).
Killestein, J., Kalkers, N. F. & Polman, C. H. Glutamate inhibition in MS: the neuroprotective properties of riluzole. J. Neurol. Sci. 233, 113–115 (2005).
Chataway, J. MS-SMART trial: a multi-arm phase 2b randomised, double blind, parallel group, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis [NCT01910259]. ECTRIMS Online Library 232077, 324 (2018).
Sulkowski, G., Dabrowska-Bouta, B., Salinska, E. & Struzynska, L. Modulation of glutamate transport and receptor binding by glutamate receptor antagonists in EAE rat brain. PLOS ONE 9, e113954 (2014).
Sulkowski, G., Dabrowska-Bouta, B., Chalimoniuk, M. & Struzynska, L. Effects of antagonists of glutamate receptors on pro-inflammatory cytokines in the brain cortex of rats subjected to experimental autoimmune encephalomyelitis. J. Neuroimmunol. 261, 67–76 (2013).
Suhs, K. W. et al. N-methyl-D-aspartate receptor blockade is neuroprotective in experimental autoimmune optic neuritis. J. Neuropathol. Exp. Neurol. 73, 507–518 (2014).
Simma, N. et al. NMDA-receptor antagonists block B-cell function but foster IL-10 production in BCR/CD40-activated B cells. Cell Commun. Signal. 12, 75 (2014).
Beeton, C. et al. Selective blockade of T lymphocyte K(+) channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Proc. Natl Acad. Sci. USA 98, 13942–13947 (2001).
Nave, K. A. Myelination and support of axonal integrity by glia. Nature 468, 244–252 (2010).
Lee, Y. et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443–448 (2012). This study demonstrates the relevance of oligodendrocytes for trophic axonal support.
Irvine, K. A. & Blakemore, W. F. Remyelination protects axons from demyelination-associated axon degeneration. Brain 131, 1464–1477 (2008).
Lau, L. W., Cua, R., Keough, M. B., Haylock-Jacobs, S. & Yong, V. W. Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nat. Rev. Neurosci. 14, 722–729 (2013).
Stoffels, J. M. et al. Fibronectin aggregation in multiple sclerosis lesions impairs remyelination. Brain 136, 116–131 (2013).
Tepavcevic, V. et al. Early netrin-1 expression impairs central nervous system remyelination. Ann. Neurol. 76, 252–268 (2014).
Mi, S. et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat. Neurosci. 8, 745–751 (2005). This study identifies LINGO1, which is now being targeted with the antibody opicinumab to enhance remyelination.
Mi, S. et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat. Med. 13, 1228–1233 (2007).
Tran, J. Q. et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol. Neuroimmunol. Neuroinflamm. 1, e18 (2014).
Cadavid, D. et al. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 16, 189–199 (2017).
Petrillo, J. et al. Initial impairment and recovery of vision-related functioning in participants with acute optic neuritis from the RENEW trial of opicinumab. J. Neuroophthalmol. 39, 153–160 (2019).
Cadavid, D. et al. Efficacy analysis of opicinumab in relapsing multiple sclerosis: the phase 2b SYNERGY trial. ECTRIMS Online Library 147038, 192 (2016).
Gregg, C. et al. White matter plasticity and enhanced remyelination in the maternal CNS. J. Neurosci. 27, 1812–1823 (2007).
Zhornitsky, S., Johnson, T. A., Metz, L. M., Weiss, S. & Yong, V. W. Prolactin in combination with interferon-beta reduces disease severity in an animal model of multiple sclerosis. J. Neuroinflammation 12, 55 (2015).
Tourbah, A. et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study. Mult. Scler. 22, 1719–1731 (2016).
Mei, F. et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat. Med. 20, 954–960 (2014). This high-throughput study identified clemastine as a potent remyelinating agent.
Green, A. J. et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet 390, 2481–2489 (2017).
Rankin, K. A. et al. Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors. J. Neurosci. 39, 2184–2194 (2019).
Deshmukh, V. A. et al. A regenerative approach to the treatment of multiple sclerosis. Nature 502, 327–332 (2013).
Moss, B. P., Rensel, M. R. & Hersh, C. M. Wellness and the role of comorbidities in multiple sclerosis. Neurotherapeutics 14, 999–1017 (2017).
Ontaneda, D., Fox, R. J. & Chataway, J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol. 14, 208–223 (2015). An important and comprehensive discussion on optimal trial design in progressive MS.
Stys, P. K., Zamponi, G. W., van Minnen, J. & Geurts, J. J. Will the real multiple sclerosis please stand up? Nat. Rev. Neurosci. 13, 507–514 (2012).
Lodygin, D. et al. β-Synuclein-reactive T cells induce autoimmune CNS grey matter degeneration. Nature 566, 503–508 (2019).
Beard, J. L., Wiesinger, J. A. & Connor, J. R. Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats. Dev. Neurosci. 25, 308–315 (2003).
Lange, S. J. & Que, L. Jr. Oxygen activating nonheme iron enzymes. Curr. Opin. Chem. Biol. 2, 159–172 (1998).
Todorich, B., Pasquini, J. M., Garcia, C. I., Paez, P. M. & Connor, J. R. Oligodendrocytes and myelination: the role of iron. Glia 57, 467–478 (2009).
de los Monteros, A. E. et al. Dietary iron and the integrity of the developing rat brain: a study with the artificially-reared rat pup. Cell. Mol. Biol. 46, 501–515 (2000).
Schulz, K., Kroner, A. & David, S. Iron efflux from astrocytes plays a role in remyelination. J. Neurosci. 32, 4841–4847 (2012).
Acknowledgements
The authors acknowledge the many trainees and collaborators who have contributed to our knowledge on multiple sclerosis. S.F. is grateful for grant support from the Medical Faculty of Ruhr-University Bochum (FoRUM). V.W.Y is grateful for operating grant support from the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada and the Alberta Innovates – Health Solutions CRIO Team program.
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S.F. and V.W.Y. have filed provisional patent applications at the US Food and Drug Administration (US patent application no. 62/412,555, entitled ‘Combination Therapy with Minocycline and Hydroxychloroquine for the Treatment of Multiple Sclerosis (MS)’ and US patent application no. 62/412,534, entitled ‘Treatment for Progressive Multiple Sclerosis’). S.F. has received travel support from Biogen Idec and Genzyme, speaker’s honoraria from Novartis, board honoraria from Celgene and grant support from Novartis, unrelated to this article. J.R.P. declares no competing interests. R.G. has received speaker’s and board honoraria from Baxter, Bayer Schering, Biogen Idec, CLB Behring, Genzyme, Merck Serono, Novartis, Stendhal, Talecris and Teva. His department has received grant support from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis and Teva. All of R.G.’s declarations are unrelated to the content of this article. V.W.Y. has received speaker’s and advisory board honoraria from Biogen, EMD Serono, Roche, Novartis, Sanofi-Genzyme and Teva, and educational grants from Biogen, EMD Serono, Roche, Novartis, Sanofi-Genzyme and Teva.
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Glossary
- Neuromyelitis optica spectrum disorder
-
Inflammatory disorder of the central nervous system mediated by disease-specific antibodies against aquaporin-4, leading to severe immune-mediated demyelination and axonal damage.
- Normal-appearing white matter
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(NAWM). An area in the white matter without obvious lesions or significant abnormalities, such as axonal damage, astrogliosis and microgliosis.
- Normal-appearing grey matter
-
(NAGM). An area in the grey matter without obvious lesions.
- Experimental autoimmune encephalitis
-
(EAE). An inflammatory animal model of multiple sclerosis, mediated by inoculation of myelin components with adjuvants.
- Gadolinium-enhancing lesions
-
T1 lesions showing contrast agent (gadolinium) enhancement on magnetic resonance imaging.
- T2 lesions
-
Hyperintense magnetic resonance imaging sequences, indicating multiple sclerosis lesion load.
- Clinically isolated syndrome
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(CIS). The first clinical episode of neurological symptoms lasting at least 24 h, with features that are indicative of multiple sclerosis.
- Astrogliosis
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An increase in the number of astrocytes due to damage.
- Periplaque white matter
-
The area around lesions in the white matter.
- Iron chelation
-
Binding of iron by a chelating agent.
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Faissner, S., Plemel, J.R., Gold, R. et al. Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat Rev Drug Discov 18, 905–922 (2019). https://doi.org/10.1038/s41573-019-0035-2
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DOI: https://doi.org/10.1038/s41573-019-0035-2
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