Remyelination in neuromyelitis optica spectrum disorder is promoted by edaravone through mTORC1 signaling activation.

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disease of the central nervous system that is manifested as secondary myelin loss. Oligodendrocyte progenitor cells (OPCs) are the principal source of myelinating oligodendrocytes (OLs) and are abundant in demyelinated regions of NMOSD patients, thus possibly representing a cellular target for pharmacological intervention. To explore the therapeutic compounds that enhance myelination due to endogenous OPCs, we screened the candidate drugs in mouse neural progenitor cell (NPC)-derived OPCs. We identified drug edaravone, which is approved by the Food and Drug Administration (FDA), as a promoter of OPC differentiation into mature OLs. Edaravone enhanced remyelination in organotypic slice cultures and in mice, even when edaravone was administered following NMO-IgG-induced demyelination, and ameliorated motor impairment in a systemic mouse model of NMOSD. The results of mechanistic studies in NMO-IgG-treated mice and the biopsy samples of the brain tissues of NMOSD patients indicated that the mTORC1 signaling pathway was significantly inhibited, and edaravone promoted OPC maturation and remyelination by activating mTORC1 signaling. Furthermore, pharmacological activation of mTORC1 signaling significantly enhanced myelin regeneration in NMOSD. Thus, edaravone is a potential therapeutic agent that promotes lesion repair in NMOSD patients by enhancing OPC maturation.

• Authors: Wenjing Luo, Huiming Xu, Li Xu, Wei Jiang, Chen Chen, Yanyu Chang, Chunxin Liu, Zhenming Tian, Xiusheng Qiu, Chichu Xie, Xuejia Li, Haijia Chen, Shuiqing Lai, Longjun Wu, Yaxiong Cui, Changyong Tang, Wei Qiu
• Journal: Glia (Glia) Vol. 71 Issue 2 Pg. 284-304 (02 2023) ISSN: 1098-1136 [Electronic] United States
• PMID: 36089914 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Wiley Periodicals LLC.

Chemical References

• Edaravone
• Mechanistic Target of Rapamycin Complex 1
• Immunoglobulin G

Topics

• Animals
• Mice
• Remyelination (physiology)
• Neuromyelitis Optica (drug therapy)
• Edaravone (metabolism)
• Myelin Sheath (metabolism)
• Oligodendroglia (metabolism)
• Cell Differentiation (physiology)
• Signal Transduction
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Immunoglobulin G