中国科学院上海药物研究所谢欣团队近期取得重要工作进展，他们研究提出，抗肿瘤药物曲美替尼可促进少突胶质细胞的生成和髓鞘的形成。相关研究成果2024年6月13日在线发表于《药理学报》杂志上。

据介绍，少突胶质细胞（OL）是从中枢神经系统（CNS）中的少突胶质前体细胞（OPC）分化而来的。脱髓鞘是许多神经系统疾病的常见特征，如多发性硬化症（MS）和脑白质营养不良。尽管髓鞘损伤后可能会发生自发的髓鞘再生，但这通常是不够的，并可能导致神经退行性变和神经功能障碍的加重。研究人员之前的工作发现，在小鼠模型中，MEK/ERK通路负调控OPC向OL分化和髓鞘再形成。

为了促进可能的临床评估，研究人员测试了几种MEK抑制剂，这些抑制剂已被FDA批准用于小鼠和人OPC向分化系统中的癌症治疗。曲美替尼是美国食品药品监督管理局批准的首个MEK抑制剂，在四种MEK抑制剂中，其体外刺激OL生成的效果最好。曲美替尼还显著增强MOG诱导的EAE模型和LPC诱导的局灶性脱髓鞘模型中的髓鞘再形成。更令人兴奋的是，曲美替尼促进了人类胚胎干细胞（ESC）来源的OPC产生MBP⁺ OL。机制研究表明，曲美替尼通过减少E2F1核转位和随后的转录活性来促进OL的产生。

总之，这一研究表明，MEK/ERK在人类和小鼠OL生成中具有相似的抑制作用。靶向MEK/ERK途径可能有助于开发新的治疗方法或重新利用现有药物治疗脱髓鞘疾病。

附：英文原文

Title: Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation

Author: Yang, Ying, Suo, Na, Cui, Shi-hao, Wu, Xuan, Ren, Xin-yue, Liu, Yin, Guo, Ren, Xie, Xin

Issue&Volume: 2024-06-13

Abstract: Oligodendrocytes (OLs) are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). Demyelination is a common feature of many neurological diseases such as multiple sclerosis (MS) and leukodystrophies. Although spontaneous remyelination can happen after myelin injury, nevertheless, it is often insufficient and may lead to aggravated neurodegeneration and neurological disabilities. Our previous study has discovered that MEK/ERK pathway negatively regulates OPC-to-OL differentiation and remyelination in mouse models. To facilitate possible clinical evaluation, here we investigate several MEK inhibitors which have been approved by FDA for cancer therapies in both mouse and human OPC-to-OL differentiation systems. Trametinib, the first FDA approved MEK inhibitor, displays the best effect in stimulating OL generation in vitro among the four MEK inhibitors examined. Trametinib also significantly enhances remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model. More exciting, trametinib facilitates the generation of MBP+ OLs from human embryonic stem cells (ESCs)-derived OPCs. Mechanism study indicates that trametinib promotes OL generation by reducing E2F1 nuclear translocation and subsequent transcriptional activity. In summary, our studies indicate a similar inhibitory role of MEK/ERK in human and mouse OL generation. Targeting the MEK/ERK pathway might help to develop new therapies or repurpose existing drugs for demyelinating diseases.

DOI: 10.1038/s41401-024-01313-9

Source: https://www.nature.com/articles/s41401-024-01313-9