PT  - JOURNAL ARTICLE
AU  - Kelsey A. Rankin
AU  - Feng Mei
AU  - Kicheol Kim
AU  - Yun-An A. Shen
AU  - Sonia R. Mayoral
AU  - Caroline Desponts
AU  - Daniel S. Lorrain
AU  - Ari J. Green
AU  - Sergio E. Baranzini
AU  - Jonah R. Chan
AU  - Riley Bove
TI  - Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors
AID  - 10.1523/JNEUROSCI.1530-18.2019
DP  - 2019 Mar 20
TA  - The Journal of Neuroscience
PG  - 2184--2194
VI  - 39
IP  - 12
4099  - http://www.jneurosci.org/content/39/12/2184.short
4100  - http://www.jneurosci.org/content/39/12/2184.full
SO  - J. Neurosci.2019 Mar 20; 39
AB  - 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 3β-hydroxysteroid-Δ8,Δ7-isomerase), 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.SIGNIFICANCE STATEMENT Therapeutics targeted at remyelination failure, which results in axonal degeneration and ultimately disease progression, represent a large unmet need in the multiple sclerosis (MS) population. Here, we have validated a tolerable European Medicines Agency-approved (U.S. Food and Drug Administration-approved in combination with conjugated estrogens) selective estrogen receptor (ER) modulator (SERM), bazedoxifene (BZA), as a potent agent of oligodendrocyte precursor cell (OPC) differentiation and remyelination. SERMs, which were developed as nuclear ER-α and ER-β agonists/antagonists, have previously been implicated in remyelination and neuroprotection, following a heavy focus on estrogens with underwhelming and conflicting results. We show that nuclear ERs are not required for SERMs to mediate their potent effects on OPC differentiation and remyelination in vivo and highlight EBP, an enzyme in the cholesterol biosynthesis pathway that could potentially act as a target for SERMs.