Gonzalez Ginez A, Hofer Matthias P, Syed Yasir A, Amaral Ana I, Rundle Jon, Rahman Saifur, Zhao Chao, Kotter Mark R N
Anne McLaren Laboratory for Regenerative Medicine, Department of Clinical Neurosciences, Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge CB2 0SZ, UK.
Sci Rep. 2016 Aug 24;6:31599. doi: 10.1038/srep31599.
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.
增强中枢神经系统（CNS）髓鞘再生被认为是改善诸如多发性硬化症等脱髓鞘疾病毁灭性后果的重要策略。先前的研究结果表明，脱髓鞘后积累的髓鞘蛋白通过调节蛋白激酶Cα（PKCα）来阻断大鼠少突胶质前体细胞（OPC）的分化，从而抑制髓鞘再生。因此，我们筛选了具有克服这种分化阻滞潜力的药物。从我们的筛选结果来看，他莫昔芬是一种体外OPC分化的强效诱导剂。我们发现他莫昔芬的作用依赖于对雌激素受体ERα、ERβ和G蛋白偶联受体30（GPR30）的调节。此外，我们证明在体内给脱髓鞘大鼠施用他莫昔芬可加速髓鞘再生。他莫昔芬是一种成熟的药物，因此作为一种髓鞘再生药物是一个有前景的候选药物，因为它不需要进行广泛的安全性测试。此外，他莫昔芬作为诱导性遗传模型的激活剂在生物医学研究中发挥着重要作用。我们的结果强调了使用此类模型时适当对照的重要性。
