title: Identification of the Kappa-Opioid Receptor as a Therapeutic Target for Oligodendrocyte Remyelination.
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 κ-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.
  
  
  
  Remyelination represents a promising strategy to achieve functional recovery in demyelinating diseases, like MS. Thus, identification of potent compounds and targets that promote remyelination represents a critically unmet need. This study reports a cluster of compounds that are highly effective in enhancing remyelination and identifies κ-opioid receptor (KOR) as a positive regulator for oligodendroglial differentiation, implicating KOR agonism as a potential strategy to accelerate remyelination.
authors.affiliation: Department of Neurology, University of California, San Francisco, California 94158, Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, 400038, China, and.
authors.forename: Feng
authors.initials: F
authors.lastname: Mei
authors.affiliation: Department of Neurology, University of California, San Francisco, California 94158.
authors.forename: Sonia R
authors.identifier: 0000-0002-7766-5743
authors.initials: SR
authors.lastname: Mayoral
authors.affiliation: Department of Pediatrics and Neurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, California 94143.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nobuta
authors.affiliation: Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, 400038, China, and.
authors.forename: Fei
authors.identifier: 0000-0002-9641-5264
authors.initials: F
authors.lastname: Wang
authors.affiliation: Inception Sciences, San Diego, California 92121.
authors.forename: Caroline
authors.identifier: 0000-0003-2581-3123
authors.initials: C
authors.lastname: Desponts
authors.affiliation: Inception Sciences, San Diego, California 92121.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Lorrain
authors.affiliation: Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, 400038, China, and.
authors.forename: Lan
authors.identifier: 0000-0002-0391-6909
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Neurology, University of California, San Francisco, California 94158, Department of Ophthalmology, University of California, San Francisco, California 94158.
authors.forename: Ari J
authors.identifier: 0000-0001-9275-3066
authors.initials: AJ
authors.lastname: Green
authors.affiliation: Department of Pediatrics and Neurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, California 94143.
authors.forename: David
authors.initials: D
authors.lastname: Rowitch
authors.affiliation: Department of Neurology, University of California, San Francisco, California 94158, Program in Neuroscience, University of California, San Francisco, California 94158.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Whistler
authors.affiliation: Department of Neurology, University of California, San Francisco, California 94158, Program in Neuroscience, University of California, San Francisco, California 94158 jonah.chan@ucsf.edu.
authors.forename: Jonah R
authors.identifier: 0000-0002-2176-1242
authors.initials: JR
authors.lastname: Chan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000503:physiopathology*; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D008297:Male; D051379:Mice; D009186:Myelin Sheath / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D009836:Oligodendroglia / Q000166:cytology* / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*
chemical_list: D017473:Receptors, Opioid, kappa
keywords: kappa-opioid receptor; oligodendrocytes; remyelination