Abstract
Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro. We show that the effects of tamoxifen rely on modulation of the estrogen receptors ERα, ERβ, and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models.
Highlights
Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis
Prompted by our previous findings[22], which showed that oligodendrocyte progenitor cells (OPCs)-differentiation-inhibiting myelin breakdown products activate protein kinase C (PKC)αsignalling, we investigated the potential of PKCαinhibitors to promote OPC differentiation in the presence of myelin protein extracts by assessing the expression of O4 (Fig. 1)
Addition of tamoxifen to OPCs plated on control substrates or to cells on myelin substrates increased the number of MBP+and CNP+cells respectively (Fig. 1c, e–i)
Summary
Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. In the central nervous system (CNS), oligodendrocytes extend processes that form highly organized membrane wraps around axons[1] These so-called myelin sheaths form the structural basis for rapid conduction of nervous impulses[1] and have important protective and trophic functions[2,3]. Failure of remyelination can occur as a consequence of insufficient recruitment of oligodendrocyte progenitor cells (OPCs) into demyelinating lesions[9]. Previous studies, including our own work, demonstrated that myelin proteins, which accumulate following demyelination, are able to inhibit remyelination by blocking the differentiation of oligodendrocyte progenitor cells (OPCs)[18,19,20]. We found that tamoxifen promoted this most effectively, albeit via an alternative mechanism
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