Nalfurafine promotes myelination in vitro and facilitates recovery from cuprizone + rapamycin‐induced demyelination in mice

• Published in: Glia Vol. 72; no. 10; pp. 1801 - 1820
• Main Authors: Wetering, Ross, Bibi, Rabia, Biggerstaff, Andy, Hong, Sheein, Pengelly, Bria, Prisinzano, Thomas E., La Flamme, Anne C., Kivell, Bronwyn M.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.10.2024; Wiley Subscription Services, Inc
• Subjects: Cell differentiation; Cells (biology); Complexity; Confocal microscopy; Cuprizone; Demyelination; Differentiation; Electron microscopy; Glial stem cells; Immunocytochemistry; Immunofluorescence; Microscopy; Motor skill; multiple sclerosis; Myelin; Myelination; nalfurafine; oligodendrocyte; Opioid receptors (type kappa); Progenitor cells; Rapamycin; Recovery; remyelination; Therapeutic targets; Thickness; Wheel running; cuprizone; differentiation; multiple sclerosis; nalfurafine; oligodendrocyte; rapamycin; remyelination
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.24583

The kappa opioid receptor has been identified as a promising therapeutic target for promoting remyelination. In the current study, we evaluated the ability of nalfurafine to promote oligodendrocyte progenitor cell (OPC) differentiation and myelination in vitro, and its efficacy in an extended, cuprizone‐induced demyelination model. Primary mouse (C57BL/6J) OPC‐containing cultures were treated with nalfurafine (0.6–200 nM), clemastine (0.01–100 μM), T3 (30 ng/mL), or vehicle for 5 days. Using immunocytochemistry and confocal microscopy, we found that nalfurafine treatment increased OPC differentiation, oligodendrocyte (OL) morphological complexity, and myelination of nanofibers in vitro. Adult male mice (C57BL/6J) were given a diet containing 0.2% cuprizone and administered rapamycin (10 mg/kg) once daily for 12 weeks followed by 6 weeks of treatment with nalfurafine (0.01 or 0.1 mg/kg), clemastine (10 mg/kg), or vehicle. We quantified the number of OLs using immunofluorescence, gross myelination using black gold staining, and myelin thickness using electron microscopy. Cuprizone + rapamycin treatment produced extensive demyelination and was accompanied by a loss of mature OLs, which was partially reversed by therapeutic administration of nalfurafine. We also assessed these mice for functional behavioral changes in open‐field, horizontal bar, and mouse motor skill sequence tests (complex wheel running). Cuprizone + rapamycin treatment resulted in hyperlocomotion, poorer horizontal bar scores, and less distance traveled on the running wheels. Partial recovery was observed on both the horizontal bar and complex running wheel tests over time, which was facilitated by nalfurafine treatment. Taken together, these data highlight the potential of nalfurafine as a remyelination‐promoting therapeutic. Main Points Nalfurafine increased oligodendrocyte progenitor cell (OPC) differentiation and nanofibers myelination in OPC cultures. In mice, nalfurafine facilitated recovery from time‐dependent cuprizone + rapamycin‐induced behavioral deficits and demyelination.