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The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation

文献类型：期刊论文

作者Cui, Shi-hao5,6; Suo, Na4,6; Yang, Ying3,5,6; Wu, Xuan2; Guo, Shi-meng6; Xie, Xin1,2,3,4,5,6
刊名ACTA PHARMACOLOGICA SINICA
出版日期2023-11-07
页码12
ISSN号1671-4083
关键词oligodendrocyte oligodendrocyte progenitor cell differentiation remyelination U73122
DOI10.1038/s41401-023-01183-7
通讯作者Xie, Xin(xxie@simm.ac.cn)
英文摘要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 17 beta-estradiol, and both compounds do activate estrogen receptors Er alpha and Er beta with low efficacy and potency, further study indicates that these compounds do not act through Er alpha and/or Er beta to 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.
WOS关键词COUPLED RECEPTOR GPR17 ; PHOSPHOLIPASE-C ; SELECTIVE-INHIBITION ; GLIAL-CELLS ; DIFFERENTIATION ; ACTIVATION ; ALPHA ; RAT ; REMYELINATION ; GLYCOPROTEIN
资助项目This work was supported by grants from the Ministry of Science and Technology of China (STI2030 Major Projects 2022ZD0204700) and the National Natural Science Foundation of China (82121005, 82003723, 82330113).[2022ZD0204700] ; Ministry of Science and Technology of China[82121005] ; Ministry of Science and Technology of China[82003723] ; Ministry of Science and Technology of China[82330113] ; National Natural Science Foundation of China
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBL GROUP
WOS记录号WOS:001096260400001
源URL[http://119.78.100.183/handle/2S10ELR8/307751]  
专题新药研究国家重点实验室
通讯作者Xie, Xin
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Cui, Shi-hao,Suo, Na,Yang, Ying,et al. The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation[J]. ACTA PHARMACOLOGICA SINICA,2023:12.
APA Cui, Shi-hao,Suo, Na,Yang, Ying,Wu, Xuan,Guo, Shi-meng,&Xie, Xin.(2023).The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation.ACTA PHARMACOLOGICA SINICA,12.
MLA Cui, Shi-hao,et al."The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation".ACTA PHARMACOLOGICA SINICA (2023):12.

入库方式： OAI收割

来源：上海药物研究所

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