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

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

机构地区：[1]State Key Laboratory of Drug Research,National Center for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]School of Pharmacy,University of Chinese Academy of Sciences,Beijing 100049,China [3]School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China [4]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China [5]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210023,China [6]Shandong Laboratory of Yantai Drug Discovery,Bohai Rim Advanced Research Institute for Drug Discovery,Yantai 264117,China

出　　处：《Acta Pharmacologica Sinica》2024年第12期2527-2539,共13页中国药理学报（英文版）

基　　金：supported by grants from the Ministry of Science and Technology of China(STI2030 Major Projects 2022ZD0204700 to XX,2022YFA1104700 to XX);the National Natural Science Foundation of China(82121005 to XX,82003723 to NS,82330113 to XX,32000504 to RG);Youth Innovation Promotion Association of the Chinese Academy of Sciences grants(2023295 to NS,2022280 to RG);Taishan Scholars Program to XX。

摘　　要：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.

关 键 词：oligodendrocyte differentiation oligodendrocyte progenitor cell REMYELINATION trametinib MEK inhibitor MEK/ERK pathway 

分 类 号：R943[医药卫生—药剂学]