TAMOXIFEN PROMOTES DIFFERENTIATION OF OLIGODENDROCYTE PROGENITORS IN VITRO
TAMOXIFEN PROMOTES DIFFERENTIATION OF OLIGODENDROCYTE PROGENITORS IN VITRO
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DOI：
10.1016/j.neuroscience.2016.01.026
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发表时间：
2016-04-05
期刊：
影响因子：
3.3
通讯作者：
Nesic, O.
中科院分区：
文献类型：
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作者：
Barratt, H. E.;Budnick, H. C.;Nesic, O.
寻找治疗破坏性脱髓鞘疾病的最有前途的治疗方法是鉴定可促进内源性少突胶质细胞前体细胞 (OPC) 分化的临床安全药物。在这里，我们证明乳腺癌药物他莫昔芬 (TMX) 具有充分的临床安全性，并在各种脱髓鞘疾病模型中证实了有益效果，可在体外刺激大鼠神经胶质祖细胞向成熟少突胶质细胞的分化。通过蛋白质印迹测量，临床适用剂量的 TMX 显着增加了 CNPase 阳性少突胶质细胞的数量和髓磷脂碱性蛋白的蛋白质水平。此外，我们还发现 OPC 分化不仅受到前药 TMX-柠檬酸盐 (TMXC) 的刺激，而且还受到两种主要 TMX 代谢物 4-羟基-TMX 和艾多昔芬的刺激。在雌激素受体 (ER) 拮抗剂 ICI182780 存在的情况下，TMXC 及其代谢物的分化作用被完全消除。与 TMXC 和 4-羟基-TMX 相比，endoxifen 也诱导星形胶质细胞生成，但与 ER 激活无关。总之，我们发现 TMX 前药及其两种主要代谢物（4-羟基-TMX 和艾多昔芬）在体外促进 ER 依赖性少突胶质细胞生成，这是以前未报道过的。鉴于 TMX 的差异化作用是通过临床安全剂量实现的，TMX 可能是 FDA 批准的最有希望治疗脱髓鞘疾病的药物之一。由 Elsevier Ltd. 代表 IBRO 出版。
The most promising therapeutic approach to finding the cure for devastating demyelinating conditions is the identification of clinically safe pharmacological agents that can promote differentiation of endogenous oligodendrocyte precursor cells (OPCs). Here we show that the breast cancer medication tamoxifen (TMX), with well-documented clinical safety and confirmed beneficial effects in various models of demyelinating conditions, stimulates differentiation of rat glial progenitors to mature oligodendrocytes in vitro. Clinically applicable doses of TMX significantly increased both the number of CNPase-positive oligodendrocytes and protein levels of myelin basic protein, measured with Western blots. Furthermore, we also found that OPC differentiation was stimulated, not only by the pro-drug TMX-citrate (TMXC), but also by two main TMX metabolites, 4-hydroxy-TMX and endoxifen. Differentiating effects of TMXC and its metabolites were completely abolished in the presence of estrogen receptor (ER) antagonist, ICI182780. In contrast to TMXC and 4-hydroxy-TMX, endoxifen also induced astrogliogenesis, but independent of the ER activation. In sum, we showed that the TMX prodrug and its two main metabolites (4-hydroxy-TMX and endoxifen) promote ER-dependent oligodendrogenesis in vitro, not reported before. Given that differentiating effects of TMX were achieved with clinically safe doses, TMX is likely one of the most promising FDA-approved drugs for the possible treatment of demyelinating diseases. Published by Elsevier Ltd. on behalf of IBRO.