Identification of the Kappa-Opioid Receptor as a Therapeutic Target for Oligodendrocyte Remyelination.

Abstract

UNLABELLED:

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.

SIGNIFICANCE STATEMENT:

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: 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
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 36 Issue 30 Pg. 7925-35 (07 27 2016) ISSN: 1529-2401 [Electronic] United States
• PMID: 27466337 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 the authors 0270-6474/16/367925-11$15.00/0.

Chemical References

• Receptors, Opioid, kappa

Topics

• Animals
• Cell Differentiation (physiology)
• Cell Proliferation (physiology)
• Cells, Cultured
• Demyelinating Diseases (drug therapy, physiopathology)
• Drug Delivery Systems (methods)
• Female
• Male
• Mice
• Myelin Sheath (physiology)
• Nerve Regeneration (physiology)
• Neurogenesis (physiology)
• Oligodendroglia (cytology, physiology)
• Receptors, Opioid, kappa (agonists, metabolism)