Abstract

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 con- taining 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), clem- astine (10 mg/kg), or vehicle. We quantified the number of OLs using immunofluores- cence, 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.

Document Type

Article

Publication Date

2024

Notes/Citation Information

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2024 The Author(s). GLIA published by Wiley Periodicals LLC.

Digital Object Identifier (DOI)

https://doi.org/10.1002/glia.24583

Funding Information

This study was supported by research grants from the Health Research Council (#18/063) and Neurological Foundation (#1815 Pro- ject Grant) and scholarships from Victoria University of Wellington. We would like to thank Lisa Woods for statistical advice, in addition to Ashley Simons, Neville Higgison, Craig Doney, Paul Roulston, and Danyl McLauchlan for technical support. Open access publishing facil- itated by Victoria University of Wellington, as part of the Wiley - Vic- toria University of Wellington agreement via the Council of Australian University Librarians.

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