Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination

Abstract

Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination—with emphasis upon myelin composition/architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure

“…Proper regulation and control of the inflammatory response is required to protect OLs from damage and to promote remyelination (Diemel, Copelman, & Cuzner, ; Marriott et al, ; Merson, Binder, & Kilpatrick, ; Petković, Campbell, Gonzalez, & Castellano, ). In demyelinating diseases such as MS, alterations in the innate immune system contribute to myelin damage, axonal loss and limit remyelination (Podbielska, Banik, Kurowska, & Hogan, ). We quantified the number of immune cells at the midline of the corpus callosum in both groups of mice and found no differences in the number of astrocytes and microglia/macrophages indicating that the recruitment of these glial cell populations are not affected by deletion of Gas6‐Axl signaling.…”

Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis

“…This precise organization enables the restriction of voltage gated sodium channels to nodes of Ranvier and voltage gated potassium channels to areas called juxtaparanodes (Pedraza et al, 2001; Rasband, 2010, 2008). Demyelination disrupts ion channel segregation (Coman et al, 2006; Wolswijk and Balesar, 2003), such that sodium and potassium channels redistribute along the axon, causing overlap of paranodal and juxtaparanodal protein domains (Craner et al, 2004; England et al, 1990; Podbielska et al, 2013; Scherer and Arroyo, 2002). The diffusion of ion channels and increased membrane capacitance from myelin loss produce an impedance mismatch in demyelinated axons, which causes inefficient conduction (Waxman, 2006).…”

Involvement of CD9 and PDGFR in migration is evolutionarily conserved from Drosophila glia to human glioma

“…The two PDGF-receptors (PDGFRa and PDGFRb) are expressed in different localizations in the adult brain. While PDGFRa is expressed in mature astrocytes and neurons [21,22], PDFGRb is expressed in pericytes, smooth muscle cells and endothelial cells as well as in neuronal cells [21]. Both PDGFRs are expressed in gliomas.…”