Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system
Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system
复制标题
DOI：
10.1038/srep31599
复制
发表时间：
2016-08-24
影响因子：
4.6
通讯作者：
Kotter, Mark R. N.
中科院分区：
文献类型：
--
作者：
Gonzalez, Ginez A.;Hofer, Matthias P.;Kotter, Mark R. N.
增强中枢神经系统（CNS）髓磷脂再生被认为是改善多发性硬化症等脱髓鞘疾病破坏性后果的重要策略。先前的研究结果表明，脱髓鞘后积累的髓鞘蛋白可通过调节 PKC α 来阻断大鼠少突胶质细胞祖细胞 (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障碍的潜力的药物。从我们的筛选来看，他莫昔芬是 OPC 体外分化的有效诱导剂。我们发现他莫昔芬的作用依赖于雌激素受体 ER α、ER β 和 GPR30 的调节。此外，我们证明对脱髓鞘大鼠体内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，因此是一种有前途的髓磷脂再生药物候选者，因为它不需要广泛的安全性测试。此外，他莫昔芬作为诱导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控制的重要性。
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 PKC alpha. 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 ER alpha, ER beta, 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.