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The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation

Acta Pharmacologica Sinica volume 45, pages 490–501 (2024)Cite this article

Abstract

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 Erα and Erβ with low efficacy and potency, further study indicates that these compounds do not act through Erα and/or Erβ 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.

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Fig. 1: U73122 promotes OPC to OL differentiation.
Fig. 2: U73122 promotes gradual expression of OL lineage markers.
Fig. 3: U73122 enhances myelination in vitro.
Fig. 4: U73122 promotes remyelination in MOG-induced EAE model.
Fig. 5: U73122 enhances OPC differentiation independent of PI-PLC.
Fig. 6: U73122 and U73343 enhance OPC differentiation independent of Erα and Erβ.
Fig. 7: U73122 and U73343 modulate cholesterol synthesis pathway in OPCs.

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Acknowledgements

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).

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Authors and Affiliations

  1. State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Shi-hao Cui, Na Suo, Ying Yang, Shi-meng Guo & Xin Xie

  2. School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China

    Shi-hao Cui, Ying Yang & Xin Xie

  3. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China

    Na Suo & Xin Xie

  4. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Ying Yang & Xin Xie

  5. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Xuan Wu & Xin Xie

  6. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China

    Xin Xie

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Contributions

SHC conducted most of the experiments. The effect of U73122 and U73343 on OPC differentiation were discovered by NS. SHC and NS analyzed the results, and wrote the paper. YY performed the co-culture experiment and part of the OPC differentiation assay. XW performed part of the western blot analysis. SMG provided technical assistance in luciferase reporter assays and IP1 detection assay. XX conceived the idea for the project, analyzed the results, and wrote the paper. All authors reviewed the results and approved the manuscript.

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Correspondence to Xin Xie.

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Cui, Sh., Suo, N., Yang, Y. et al. The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation. Acta Pharmacol Sin 45, 490–501 (2024). https://doi.org/10.1038/s41401-023-01183-7

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