Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery

Abstract

Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination.DOI: http://dx.doi.org/10.7554/eLife.18246.001

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

“…Preclinical work validated the efficacy of clemastine fumarate in vitro and in animal models. 17,19 Additional work confirmed the efficacy of clemastine fumarate in multiple animal models [17][18][19][20][21][22] and showed that this benefit was mediated specifically via remyelination induced from oligo dendrocyte differentiation and not via effects on the immune system. 19 We furthermore showed the capacity of clemastine fumarate to induce oligodendrocyte progenitor cell (OPC) differentiation and myelination with human OPCs (appendix).…”

“…Preclinical data unequivocally showed that clemastine fumarate promotes oligodendrocyte precursor differentiation 17,18 and remyelination [19][20][21][22] without modulating the immune system. 19 The robustness of the findings were documented by the latency improvement observed in both groups of the cohort while on active treatment. Furthermore, the sustained clinical response in the first epoch provides evidence that the observed improvement was not due to a transient effect of medication on electrical conductance but rather reflects a persistent structural change induced by treatment.…”

Multiple sclerosis animal models: a clinical and histopathological perspective

“…The term Cup/EAE model refers to a recently developed novel MS animal model in our group (115 Histopathologic characteristics of an acute, inflammatory MS lesion within the white matter. When a demyelinated axon undergoes remyelination and the extent of axonal damage is compensated by, for example, neuronal plasticity complete clinical recovery might occur during the remission phase (62,89). The entire lesion is interspersed with activated monocytes and microglia, expressing MHC-II protein.…”

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

“…Notably, remyelination may be slowed by cytotoxicity near the lesion, insufficient tissue oxygenation (Tsai et al, ; Yuen et al, ), or inhibitory factors in the glial scar and myelin debris (Buss & Schwab, ; Church, Milich, Lerch, Popovich, & McTigue, ; Dyck et al, ; Dyck, Kataria, Akbari‐Kelachayeh, Silver, & Karimi‐Abdolrezaee, ; Keough et al, ; Plemel, Manesh, Sparling, & Tetzlaff, ). Accelerated remyelination is sufficient to preserve axons following T‐cell mediated demyelination (Mei et al, ). Rapid remyelination may restore metabolic support of the axon to the oligodendrocyte (Philips & Rothstein, ; Saab & Nave, ), protect against inflammatory mediators like nitric oxide (Redford et al, ), and calcium accumulation within the axon (Witte et al, ).…”