Remyelination Therapy in Multiple Sclerosis

Harlow, Danielle E.; Honce, Justin M.; Miravalle, Augusto

doi:10.3389/fneur.2015.00257

Cited by 68 publications

(50 citation statements)

References 191 publications

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“…Based on the evidence that remyelination failure is more commonly associated with the impairment of the final stage of oligodendrocyte developmental program25, strategies to enhance remyelination are frequently designed to promote OPC differentiation into new myelinating oligodendrocytes31. However, several remyelinating molecules have been described to promote both proliferation and differentiation323334 or proliferation alone35.…”

Section: Discussionmentioning

confidence: 99%

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Eleuteri

Olla

Veroni

et al. 2017

Sci Rep

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There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

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Section: Discussionmentioning

confidence: 99%

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Eleuteri

Olla

Veroni

et al. 2017

Sci Rep

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“…Besides, high cost and side effect of DMT is also unfavorable for MS patients (Adelman et al, 2013; Carrithers, 2014; Winkelmann et al, 2015). The process of remyelination is directly and closely related to the restoration of neuronal function and the amelioration of clinical disabilities (Nave, 2010; Harlow et al, 2015; Olsen and Akirav, 2015). However, DMTs have limited impact on remyelination.…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture Promotes Remyelination after Cuprizone Treatment by Enhancing Myelin Debris Clearance

et al. 2017

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Promoting remyelination is crucial for patients with demyelinating diseases including multiple sclerosis. However, it is still a circuitous conundrum finding a practical remyelinating therapy. Electroacupuncture (EA), originating from traditional Chinese medicine (TCM), has been widely used to treat CNS diseases all over the world, but the role of EA in demyelinating diseases is barely known. In this study, we examined the remyelinating properties and mechanisms of EA in cuprizone-induced demyelinating model, a CNS demyelinating murine model of multiple sclerosis. By feeding C57BL/6 mice with chow containing 0.2% cuprizone for 5 weeks, we successfully induce demyelination as proved by weight change, beam test, pole test, histomorphology, and Western Blot. EA treatment significantly improves the neurobehavioral performance at week 7 (2 weeks after withdrawing cuprizone chow). RNA-seq and RT-PCR results reveal up-regulated expression of myelin-related genes, and the expression of myelin associated protein (MBP, CNPase, and O4) are also increased after EA treatment, indicating therapeutic effect of EA on cuprizone model. It is widely acknowledged that microglia exert phagocytic effect on degraded myelin debris and clear these detrimental debris, which is a necessary process for subsequent remyelination. We found the remyelinating effect of EA is associated with enhanced clearance of degraded myelin debris as detected by dMBP staining and red oil O staining. Our further studies suggest that more microglia assemble in demyelinating area (corpus callosum) during the process of EA treatment, and cells inside corpus callosum are mostly in a plump, ameboid, and phagocytic shape, quite different from the ramified cells outside corpus callosum. RNA-seq result also unravels that most genes relating to positive regulation of phagocytosis (GO:0050766) are up-regulated, indicating enhanced phagocytic process after EA treatment. During the process of myelin debris clearance, microglia tend to change their phenotype toward M2 phenotype. Thus, we also probed into the phenotype of microglia in our study. Immuno-staining results show increased expression of CD206 and Arg1, and the ratio of CD206/CD16/32 are also higher in EA group. In conclusion, these results demonstrate for the first time that EA enhances myelin debris removal from activated microglia after demyelination, and promotes remyelination.

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“…Remyelination develops in two steps: the colonization of the lesions by the OPCs, and the OPC differentiation into mature oligodendrocytes able to generate functional myelin sheath [127]. The factors that could interfere with the OPC abilities to remyelinating in MS have been reviewed [128][129][130].…”

Section: Remyelination Strategiesmentioning

confidence: 99%