Identification of the kappa-opioid receptor as a therapeutic target for oligodendrocyte remyelination

Feng Mei, Sonia R. Mayoral, Hiroko Nobuta, Fei Wang, Caroline Desponts, Daniel S. Lorrain, Lan Xiao, Ari J. Green, David Rowitch, Jennifer Whistler, Jonah R. Chan

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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 -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.

Original languageEnglish (US)
Pages (from-to)7925-7935
Number of pages11
JournalJournal of Neuroscience
Volume36
Issue number30
DOIs
StatePublished - Jul 27 2016
Externally publishedYes

Keywords

  • Kappa-opioid receptor
  • Oligodendrocytes
  • Remyelination

ASJC Scopus subject areas

  • Neuroscience(all)

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    Mei, F., Mayoral, S. R., Nobuta, H., Wang, F., Desponts, C., Lorrain, D. S., Xiao, L., Green, A. J., Rowitch, D., Whistler, J., & Chan, J. R. (2016). Identification of the kappa-opioid receptor as a therapeutic target for oligodendrocyte remyelination. Journal of Neuroscience, 36(30), 7925-7935. https://doi.org/10.1523/JNEUROSCI.1493-16.2016