The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation  

作　　者：Shi-hao Cui Na Suo Ying Yang Xuan Wu Shi-meng 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 Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China [4]School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,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3期490-501,共12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);the National Natural Science Foundation of China(82121005,82003723,82330113).

摘　　要：Oligodendrocytes(OLs)are glial cells that ensheath neuronal axons and form myelin in the central nervous system(CNS).OLs are differentiated from oligodendrocyte precursor cells(OPCs)during development and myelin repair,which is often insufficient in the latter case in demyelinating diseases such as multiple sclerosis(MS).Many factors have been reported to regulate OPC-to-OL differentiation,including a number of G protein-coupled receptors(GPCRs).In an effort to search pathways downstream of GPCRs that might be involved in OPC differentiation,we discover that U73122,a phosphoinositide specific phospholipase C(PI-PLC)inhibitor,dramatically promotes OPC-to-OL differentiation and myelin regeneration in experimental autoimmune encephalomyelitis model.Unexpectedly,U73343,a close analog of U73122 which lacks PI-PLC inhibitory activity also promotes OL differentiation,while another reported PI-PLC inhibitor edelfosine does not have such effect,suggesting that U73122 and U73343 enhance OPC differentiation independent of PLC.Although the structures of U73122 and U73343 closely resemble 17β-estradiol,and both compounds do activate estrogen receptors Erαand Erβwith low efficacy and potency,further study indicates that these compounds do not act through Erαand/or Erβto promote OPC differentiation.RNA-Seq and bioinformatic analysis indicate that U73122 and U73343 may regulate cholesterol biosynthesis.Further study shows both compounds increase 14-dehydrozymostenol,a steroid reported to promote OPC differentiation,in OPC culture.In conclusion,the aminosteroids U73122 and U73343 promote OPC-to-OL generation and myelin formation by regulating cholesterol biosynthesis pathway.

关 键 词：OLIGODENDROCYTE oligodendrocyte progenitor cell DIFFERENTIATION REMYELINATION U73122 

分 类 号：R96[医药卫生—药理学]