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

A significant unmet need for patients with multiple sclerosis (MS) is the lack of U.S. Food and Drug Administration (FDA)-approved remyelinating therapies. We have identified a compelling remyelinating agent, bazedoxifene (BZA), a European Medicines Agency (EMA)-approved (and FDA-approved in combination with conjugated estrogens) selective estrogen receptor (ER) modulator (SERM) that could move quickly from bench to bedside. This therapy stands out as a tolerable alternative to previously identified remyelinating agents and other candidates within this family. Using an unbiased high-throughput screen, with subsequent validation in both murine and human oligodendrocyte precursor cells (OPCs) and coculture systems, we find that BZA enhances differentiation of OPCs into functional oligodendrocytes. Using an in vivo murine model of focal demyelination, we find that BZA enhances OPC differentiation and remyelination. Of critical importance, we find that BZA acts independently of its presumed target, the ER, in both in vitro and in vivo systems. Using a massive computational data integration approach, we independently identify six possible candidate targets through which SERMs may mediate their effect on remyelination. Of particular interest, we identify EBP (encoding 3␤-hydroxysteroid-⌬8,⌬7isomerase), a key enzyme in the cholesterol biosynthesis pathway, which was previously implicated as a target for remyelination. These findings provide valuable insights into the implications for SERMs in remyelination for MS and hormonal research at large.

Background: Five case series reported increased relapse risk after assisted reproductive technologies (ART) in women with multiple sclerosis (MS), but small numbers and heterogeneous study design limit broader conclusions. Objective: To evaluate the risk of relapses after ART in an independent case series and in aggregated analyses of existing studies. Methods: We compared annualized relapse rate (ARR) in the 3 months after, and 12 months before, ART in (1) an unpublished cohort (Boston: prospectively collected relapses; 22 ART cycles), (2i) data pooled from Boston and five published studies (164 cycles), and (2ii) a meta-analysis of all case series published by 2017 (220 cycles; PRISMA and MOOSE guidelines). Results: In the Boston cohort, mean ARR was not higher after ART than before (mean: 0.18 ± 0.85 vs 0.27 ± 0.55, p = 0.58). In the pooled analyses, ARR was significantly higher after ART for all clinical scenarios, including varying ART protocols ( p ⩽ 0.01 for each). The meta-analysis confirmed an increased ARR after ART (mean difference (MD) = 0.92, 95% confidence interval (CI) = [0.33, 1.51], p = 0.01). Conclusion: These pooled data support an increase in ARR following ART. Reasons for local variation in ARR after ART, and consideration of MS treatments during conception attempts, will be pursued.

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This article summarizes what is known about the disease course in women with MS, how it differs from men, and the current state of knowledge regarding effects of reproductive exposures (menarche, childbearing, menopause) on MS-related inflammation and neurodegeneration. Recent findings regarding pregnancy-associated relapses in the treatment era, protective effects of breastfeeding, and care for women during the menopausal transition are reviewed. Then, updated recommendations to guiding women during childbearing-including pre-conception counseling, discontinuation of MS therapies, and management of postpartum relapses-are provided. Whenever possible, areas of uncertainty and avenues for future research are highlighted. From childhood through the postreproductive life stages, gender and hormonal exposures appear to shape an individual's risk for MS, as well as the experience of living with MS.