Pharmacological possibilities of modulating remyelination in multiple sclerosis Review article
Article Sidebar
Published:
Jun 30, 2023
Keywords:
multiple sclerosis, remyelination, oligodendrocytes
Main Article Content
Abstract
Significant progress in the treatment of multiple sclerosis has resulted in a decrease in the frequency of exacerbations in patients receiving therapy. An important challenge remains to inhibit the progression of the disease’s disability, which is, among other things, the result of cumulative axonal damage. Loss of myelin sheath impairs axon function, and permanent demyelination leaves axons vulnerable to irreversible changes. Spontaneous endogenous remyelination processes are insufficient to stop the progression of axonal damaging processes. Understanding the mechanisms regulating remyelination opens up the potential for the use of new molecules that stimulate the reconstruction of the myelin sheath.
Article Details
Issue
Section
Articles
Copyright © by Medical Education. All rights reserved.
References
1. Scolding N, Barnes D, Cader S et al. Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis. Pract Neurol. 2015; 15(4): 273.
2. Ebers GC. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998; 352(9139): 1498-504.
3. Johnson KP, Brooks BR, Cohen JA et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis. Neurology. 1995; 45(7): 1268.
4. Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367(12): 1098-107.
5. Confavreux C, O’Connor P, Comi G et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo- controlled, phase 3 trial. Lancet Neurol. 2014; 13(3): 247-56.
6. Calabresi PA, Radue E-W, Goodin D et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014; 13(6): 545-56.
7. Giovannoni G, Comi G, Cook S et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010; 362(5): 416-26.
8. Franklin RJM, French-Constant C. Regenerating CNS myelin – from mechanisms to experimental medicines. Nat Rev Neurosci. 2017; 18: 753.
9. Smith KJ, McDonald WI. The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease. Philos Trans R Soc Lond B Biol Sci. 1999; 354(1390): 1649-73.
10. Smith KJ, Blakemore WF, McDonald WI. Central remyelination restores secure conduction. Nature. 1979; 280(5721): 395-6.
11. Patrikios P, Stadelmann C, Kutzelnigg A et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain. 2006; 129(12): 3165-72.
12. Jeffries MA, Urbanek K, Torres L et al. ERK1/2 Activation in preexisting oligodendrocytes of adult mice drives new myelin synthesis and enhanced CNS function. J Neurosci. 2016; 36(35): 9186-200.
13. Psachoulia K, Jamen F, Young KM et al. Cell cycle dynamics of NG2 cells in the postnatal and ageing brain. Neuron Glia Biol. 2009; 5(3-4): 57-67.
14. Menn B, Garcia-Verdugo JM, Yaschine C et al. Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci. 2006; 26(30): 7907.
15. French-Constant C, Raff MC. Proliferating bipotential glial progenitor cells in adult rat optic nerve. Nature. 1986; 319: 499.
16. Zawadzka M, Rivers LE, Fancy SPJ et al. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell. 2010; 6(6): 578-90.
17. Blakemore WF. Pattern of remyelination in the CNS. Nature. 1974; 249(5457): 577-8.
18. Wolswijk G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci. 1998; 18(2): 601.
19. Hughes EG, Kang SH, Fukaya M et al. Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nat Neurosci. 2013; 16(6): 668-76.
20. Liddelow SA, Guttenplan KA, Clarke LE et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017; 18(541): 481.
21. Klingseisen A, Lyons DA. Axonal regulation of central nervous system myelination: structure and function. Neuroscientist. 2017; 24(1): 7-21.
22. Frischer JM, Weigand SD, Guo Y et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol. 2015; 78(5): 710-21.
23. Goldschmidt T, Antel J, König FB et al. Remyelination capacity of the MS brain decreases with disease chronicity. Neurology. 2009; 72(22): 1914.
24. Shields SA, Gilson JM, Blakemore WF et al. Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination. Glia. 1999; 28(1): 77-83.
25. Hampton DW, Innes N, Merkler D et al. Focal immune-mediated white matter demyelination reveals an age-associated increase in axonal vulnerability and decreased remyelination efficiency. Am J Pathol. 2012; 180(5): 1897-905.
26. Neumann B, Baror R, van Wijngaarden P et al. Remyelination of regenerating axons. Acta Ophthalmola. 2017; 95(S259).
27. Rawji KS, Yong VW. The benefits and detriments of macrophages/microglia in models of multiple sclerosis. Clin Dev Immunol. 2013: 948976.
28. Döring A, Sloka S, Lau L et al. Stimulation of monocytes, macrophages, and microglia by amphotericin B and macrophage colony-stimulating factor promotes remyelination. J Neurosci. 2015; 35(3): 1136.
29. Yong VW, Rivest S. Taking advantage of the systemic immune system to cure brain diseases. Neuron. 2009; 64(1): 55-60.
30. Sedel F, Bernard D, Mock DM et al. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2016; 1(110): 644-53.
31. Tourbah A, Lebrun-Frenay C, Edan G et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. 2016; 22(13): 1719-31.
32. Tourbah A, Gout O, Vighetto A et al. MD1003 (high-dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, placebo-controlled study. CNS Drugs. 2018; 32(7): 661-72.
33. Grove RA, Harrington CM, Mahler A et al. A randomized, double-blind, placebo-controlled, 16-week study of the H3 receptor antagonist, GSK239512 as a monotherapy in subjects with mild-to-moderate Alzheimer’s disease. Curr Alzheimer Res. 2014; 11(1): 47-58.
34. Chen Y, Zhen W, Guo T et al. Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination. PLoS ONE. 2017; 12(12): e0189380-e0189380.
35. Schwartzbach CJ, Grove RA, Brown R et al. Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study. J Neurol. 2017; 264(2): 304-15.
36. Mei F, Lehmann-Horn K, Shen Y-AA et al. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. Elife. 2016; 5: e18246.
37. Mei F, Fancy SPJ, Shen Y-AA et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014; 20(8): 954-60.
38. Green AJ, Gelfand JM, Cree BA et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017; 390(10111): 2481-9.
39. Mi S, Miller RH, Lee X et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci. 2005; 15(8): 745.
40. Zhang Y, Zhang YP, Pepinsky B et al. Inhibition of LINGO-1 promotes functional recovery after experimental spinal cord demyelination. Exp Neurol. 2015; 1(266): 68-73.
41. Tran JQ, Rana J, Barkhof F et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm. 2014; 1(2): e18-e18.
42. Cadavid D, Balcer L, Galetta S et al. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2017; 16(3): 189-99.
43. Mellion M, Edwards KR, Hupperts R et al. Efficacy results from the phase 2b SYNERGY study: treatment of disabling multiple sclerosis with the Anti-LINGO-1 monoclonal antibody opicinumab (S33.004). Neurology. 2017; 88(16 suppl): S33.004.
44. Kipp M. Does siponimod exert direct effects in the central nervous system? Cells. 2020; 9(8): 1771.
45. Mannioui A, Vauzanges Q, Fini JB et al. The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination. Mult Scler. 2018; 24(11): 1421-32.
2. Ebers GC. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998; 352(9139): 1498-504.
3. Johnson KP, Brooks BR, Cohen JA et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis. Neurology. 1995; 45(7): 1268.
4. Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367(12): 1098-107.
5. Confavreux C, O’Connor P, Comi G et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo- controlled, phase 3 trial. Lancet Neurol. 2014; 13(3): 247-56.
6. Calabresi PA, Radue E-W, Goodin D et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014; 13(6): 545-56.
7. Giovannoni G, Comi G, Cook S et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010; 362(5): 416-26.
8. Franklin RJM, French-Constant C. Regenerating CNS myelin – from mechanisms to experimental medicines. Nat Rev Neurosci. 2017; 18: 753.
9. Smith KJ, McDonald WI. The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease. Philos Trans R Soc Lond B Biol Sci. 1999; 354(1390): 1649-73.
10. Smith KJ, Blakemore WF, McDonald WI. Central remyelination restores secure conduction. Nature. 1979; 280(5721): 395-6.
11. Patrikios P, Stadelmann C, Kutzelnigg A et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain. 2006; 129(12): 3165-72.
12. Jeffries MA, Urbanek K, Torres L et al. ERK1/2 Activation in preexisting oligodendrocytes of adult mice drives new myelin synthesis and enhanced CNS function. J Neurosci. 2016; 36(35): 9186-200.
13. Psachoulia K, Jamen F, Young KM et al. Cell cycle dynamics of NG2 cells in the postnatal and ageing brain. Neuron Glia Biol. 2009; 5(3-4): 57-67.
14. Menn B, Garcia-Verdugo JM, Yaschine C et al. Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci. 2006; 26(30): 7907.
15. French-Constant C, Raff MC. Proliferating bipotential glial progenitor cells in adult rat optic nerve. Nature. 1986; 319: 499.
16. Zawadzka M, Rivers LE, Fancy SPJ et al. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell. 2010; 6(6): 578-90.
17. Blakemore WF. Pattern of remyelination in the CNS. Nature. 1974; 249(5457): 577-8.
18. Wolswijk G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci. 1998; 18(2): 601.
19. Hughes EG, Kang SH, Fukaya M et al. Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nat Neurosci. 2013; 16(6): 668-76.
20. Liddelow SA, Guttenplan KA, Clarke LE et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017; 18(541): 481.
21. Klingseisen A, Lyons DA. Axonal regulation of central nervous system myelination: structure and function. Neuroscientist. 2017; 24(1): 7-21.
22. Frischer JM, Weigand SD, Guo Y et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol. 2015; 78(5): 710-21.
23. Goldschmidt T, Antel J, König FB et al. Remyelination capacity of the MS brain decreases with disease chronicity. Neurology. 2009; 72(22): 1914.
24. Shields SA, Gilson JM, Blakemore WF et al. Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination. Glia. 1999; 28(1): 77-83.
25. Hampton DW, Innes N, Merkler D et al. Focal immune-mediated white matter demyelination reveals an age-associated increase in axonal vulnerability and decreased remyelination efficiency. Am J Pathol. 2012; 180(5): 1897-905.
26. Neumann B, Baror R, van Wijngaarden P et al. Remyelination of regenerating axons. Acta Ophthalmola. 2017; 95(S259).
27. Rawji KS, Yong VW. The benefits and detriments of macrophages/microglia in models of multiple sclerosis. Clin Dev Immunol. 2013: 948976.
28. Döring A, Sloka S, Lau L et al. Stimulation of monocytes, macrophages, and microglia by amphotericin B and macrophage colony-stimulating factor promotes remyelination. J Neurosci. 2015; 35(3): 1136.
29. Yong VW, Rivest S. Taking advantage of the systemic immune system to cure brain diseases. Neuron. 2009; 64(1): 55-60.
30. Sedel F, Bernard D, Mock DM et al. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2016; 1(110): 644-53.
31. Tourbah A, Lebrun-Frenay C, Edan G et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. 2016; 22(13): 1719-31.
32. Tourbah A, Gout O, Vighetto A et al. MD1003 (high-dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, placebo-controlled study. CNS Drugs. 2018; 32(7): 661-72.
33. Grove RA, Harrington CM, Mahler A et al. A randomized, double-blind, placebo-controlled, 16-week study of the H3 receptor antagonist, GSK239512 as a monotherapy in subjects with mild-to-moderate Alzheimer’s disease. Curr Alzheimer Res. 2014; 11(1): 47-58.
34. Chen Y, Zhen W, Guo T et al. Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination. PLoS ONE. 2017; 12(12): e0189380-e0189380.
35. Schwartzbach CJ, Grove RA, Brown R et al. Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study. J Neurol. 2017; 264(2): 304-15.
36. Mei F, Lehmann-Horn K, Shen Y-AA et al. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. Elife. 2016; 5: e18246.
37. Mei F, Fancy SPJ, Shen Y-AA et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014; 20(8): 954-60.
38. Green AJ, Gelfand JM, Cree BA et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017; 390(10111): 2481-9.
39. Mi S, Miller RH, Lee X et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci. 2005; 15(8): 745.
40. Zhang Y, Zhang YP, Pepinsky B et al. Inhibition of LINGO-1 promotes functional recovery after experimental spinal cord demyelination. Exp Neurol. 2015; 1(266): 68-73.
41. Tran JQ, Rana J, Barkhof F et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm. 2014; 1(2): e18-e18.
42. Cadavid D, Balcer L, Galetta S et al. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2017; 16(3): 189-99.
43. Mellion M, Edwards KR, Hupperts R et al. Efficacy results from the phase 2b SYNERGY study: treatment of disabling multiple sclerosis with the Anti-LINGO-1 monoclonal antibody opicinumab (S33.004). Neurology. 2017; 88(16 suppl): S33.004.
44. Kipp M. Does siponimod exert direct effects in the central nervous system? Cells. 2020; 9(8): 1771.
45. Mannioui A, Vauzanges Q, Fini JB et al. The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination. Mult Scler. 2018; 24(11): 1421-32.