期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 30, 页码 7925-7935出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1493-16.2016
关键词
kappa-opioid receptor; oligodendrocytes; remyelination
资金
- US National Multiple Sclerosis Society [RG5203A4]
- NIH/NINDS [R01NS062796]
- Rachleff Endowment
- Overseas Youth Program Grant of the Third Military Medical University
- National Natural Science Foundation of China [NSFC81270017]
- NIH/NIGMS IRACDA Postdoctoral Fellowship [K12GM081266]
- Joint Research Fund for Overseas Chinese Young Scholars Chongqing Scientific and Technical Innovation Foundation of China [NSCF 31228011, CSTCKJCXLJRC07]
Remyelinating therapies seek to promote restoration of function and normal cellular architecture following demyelination in diseases, such as multiple sclerosis (MS). Functional screening for small molecules or novel targets for remyelination is a major hurdle to the identification and development of rational therapeutics for MS. Recent findings and technical advances provide us with a unique opportunity to provide insight into the cell autonomous mechanisms for remyelination and address this unmet need. Upon screening a G-protein-coupled receptor small-molecule library, we report the identification of a cluster of kappa-opioid receptor (KOR) agonists that significantly promotes oligodendrocyte differentiation and myelination. KOR agonists were validated in purified rat oligodendroglial cultures, and the (+/-)U-50488 compound proved to be most effective for differentiation. (+/-)U-50488 treatment significantly enhances differentiation and myelination in purified oligodendroglial cocultures and greatly accelerates the kinetics of remyelination in vivo after focal demyelination with lysolecithin. The effect of (+/-)U-50488 is attenuated by KOR antagonists and completely abolished in KOR-null oligodendroglia. Conditional deletion of KOR in murine oligodendrocyte precursor cells (OPCs) greatly inhibits remyelination after focal demyelination lacking any response to (+/-)U-50488 treatment. To determine whether agonism of KOR represents a feasible therapeutic approach, human induced pluripotent stem cell-derived OPCs were treated with (+/-)U-50488. Consistent with findings, differentiation of human OPCs into mature oligodendrocytes was significantly enhanced. Together, KOR is a therapeutic target to consider for future remyelination therapy.
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