Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors

Abstract

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.

Remyelination alters the pattern of myelin in the cerebral cortex

“…As recent studies suggest that even subtle changes in oligodendrogenesis can alter behavioral performance (McKenzie et al, 2014; Xiao et al, 2016), the impact of these changes may be profound. The ability to monitor the regeneration of myelin sheaths with high spatial and temporal resolution in vivo within defined circuits provides new opportunities to evaluate the effectiveness of potential therapeutic interventions (Deshmukh et al, 2013; Early et al, 2018; Mei et al, 2014; Rankin et al, 2019) and a platform to explore the functional consequences of myelin reorganization.…”

Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury

“…To ascertain whether NFIA demonstrates region-specific functions in reactive astrocytes, we performed lysolecithin lesioning in the corpus callosum of the adult brain, using the NFIA fl/fl GFAP-CreER mouse lines and the tamoxifen induction paradigm shown in Figure 2K. Oligodendrocyte regeneration was evaluated 12 dpl of the corpus callosum, a relatively early time point in the myelin repair process for this region (27). Our analysis revealed no changes in the extent of oligodendrocyte differentiation or in the production of reactive astrocytes in these lesions (Supplemental Figure 4), indicating that loss of NFIA does not influence repair in this context.…”

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

“…However, it cannot be excluded that these agents may also affect lipid biosynthesis on other neural cells. Among them, clemastine, benztropine, and some selective estrogen receptor modulators (SERM) inhibit the enzyme EBP, whereas miconazole and ketoconazole, two imidazole antifungals, act through the inhibition of the enzyme CYP51, all ultimately leading to the accumulation of the two 8,9 unsaturated sterols zymosterol and lanosterol, respectively [54,55]. It is worth to mention that alternative mechanisms of action may contribute to a direct increase of OL differentiation.…”

“…the enzyme CYP51, all ultimately leading to the accumulation of the two 8,9 unsaturated sterols zymosterol and lanosterol, respectively [54,55]. It is worth to mention that alternative mechanisms of action may contribute to a direct increase of OL differentiation.…”

“…Interestingly, these positive effects were maintained when the experiment was performed in ERα-ERβ double knock-out mice, suggesting that BZA act through an ER-independent mechanism. Indeed, a sophisticated computational analysis identified EBP as one out of the six possible candidate targets through which BZA and other SERMs, such as tamoxifen, could promote remyelination [55]. The strong pre-clinical evidence for the remyelinating potential of BZA prompted a phase 2 randomized, placebo controlled, double-blind, delayed-start trial, now at the initial stage (ReWRAP, NCT04002934).…”