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In the current study, we evaluated the ability of nalfurafine to promote oligodendrocyte progenitor cell (OPC) differentiation and myelination <jats:italic>in vitro<\/jats:italic>, and its efficacy in an extended, cuprizone\u2010induced demyelination model. Primary mouse (C57BL\/6J) OPC\u2010containing cultures were treated with nalfurafine (0.6\u2013200\u2009nM), clemastine (0.01\u2013100\u2009\u03bcM), T3 (30\u2009ng\/mL), or vehicle for 5\u2009days. Using immunocytochemistry and confocal microscopy, we found that nalfurafine treatment increased OPC differentiation, oligodendrocyte (OL) morphological complexity, and myelination of nanofibers <jats:italic>in vitro<\/jats:italic>. Adult male mice (C57BL\/6J) were given a diet containing 0.2% cuprizone and administered rapamycin (10\u2009mg\/kg) once daily for 12\u2009weeks followed by 6\u2009weeks of treatment with nalfurafine (0.01 or 0.1\u2009mg\/kg), clemastine (10\u2009mg\/kg), or vehicle. We quantified the number of OLs using immunofluorescence, gross myelination using black gold staining, and myelin thickness using electron microscopy. Cuprizone\u2009+\u2009rapamycin 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\u2010field, horizontal bar, and mouse motor skill sequence tests (complex wheel running). Cuprizone\u2009+\u2009rapamycin 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\u2010promoting therapeutic.<\/jats:p>","DOI":"10.1002\/glia.24583","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T11:29:42Z","timestamp":1718882982000},"page":"1801-1820","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Nalfurafine promotes myelination <scp><i>in vitro<\/i><\/scp> and facilitates recovery from cuprizone\u2009+ rapamycin\u2010induced demyelination in mice"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1387-444X","authenticated-orcid":false,"given":"Ross","family":"van de Wetering","sequence":"first","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabia","family":"Bibi","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Biggerstaff","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheein","family":"Hong","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bria","family":"Pengelly","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0649-8052","authenticated-orcid":false,"given":"Thomas E.","family":"Prisinzano","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2344-7281","authenticated-orcid":false,"given":"Anne C.","family":"La Flamme","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"},{"name":"Malaghan Institute of Medical Research  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9699-553X","authenticated-orcid":false,"given":"Bronwyn M.","family":"Kivell","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery Victoria University of Wellington  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(98)00151-9"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.7554\/ELIFE.23329"},{"issue":"1","key":"e_1_2_8_4_1","first-page":"489","article-title":"Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats","volume":"264","author":"Bals\u2010Kubik R.","year":"1993","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1006\/MCNE.1999.0827"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.CUB.2015.07.056"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/CDLI.7.5.719-723.2000"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.JNEUROIM.2018.03.020"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba6905"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/S00213-010-1806-Y\/FIGURES\/2"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3769-07.2007"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M513640200"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/ACSCHEMNEURO.0C00407\/ASSET\/IMAGES\/LARGE\/CN0C00407_0006.JPEG"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/FNCEL.2020.575082"},{"key":"e_1_2_8_15_1","doi-asserted-by":"crossref","unstructured":"Chang A. 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