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

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.

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Fig. 1: Trametinib promotes OL generation from NPC-derived OPCs.
Fig. 2: Trametinib promotes OL generation from primary NG2+ OPCs.
Fig. 3: Trametinib promotes gradual expression of OL lineage markers.
Fig. 4: Trametinib promotes OL generation via E2F1.
Fig. 5: Trametinib promotes remyelination in MOG-induced EAE model.
Fig. 6: Trametinib promotes myelin recovery in LPC-induced demyelination model.
Fig. 7: Trametinib enhances hOL generation.

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Acknowledgements

This work was 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), and Taishan Scholars Program to XX. We thank all the staffs at the Advanced Center for Electron Microscopy, Shanghai Institute of Materia Medica (SIMM) for providing technical support for electron microscope analysis.

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YY and NS designed and conducted most of the experiments, analyzed the results, and wrote the paper; SHC and YL provided technical assistance in animal study; XW and XYR provided technical support for some cell experiments; RG provided some critical suggestions for the study; XX conceived the idea and supervise the study, analyzed the results, and wrote the paper. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Xin Xie.

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Yang, Y., Suo, N., Cui, Sh. et al. Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01313-9

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