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The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair\/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non\u2010specific immunosuppressive molecules\/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA\u2010approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup> ATPase inhibitor), originally identified as pro\u2010myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female na\u00efve C57BL\/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG<jats:sub>35\u201055<\/jats:sub>\u2010induced Th1\/Th17\u2010mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide\u2010co\u2010glycolide) nanoparticles coupled with MOG<jats:sub>35\u201055<\/jats:sub> (PLG\u2010MOG<jats:sub>35\u201055<\/jats:sub>) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre\u2010clinical evidence supporting future clinical trials of myelin\u2010specific tolerance with myelin repair\/regeneration drugs, such as digoxin, in MS patients.<\/jats:p>","DOI":"10.1002\/glia.24231","type":"journal-article","created":{"date-parts":[[2022,7,9]],"date-time":"2022-07-09T16:54:20Z","timestamp":1657385660000},"page":"1950-1970","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in <scp>chemically\u2010induced<\/scp> and <scp>immune\u2010mediated<\/scp> mouse models of multiple sclerosis"],"prefix":"10.1002","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2327-9791","authenticated-orcid":false,"given":"Haley E.","family":"Titus","sequence":"first","affiliation":[{"name":"Department of Microbiology\u2010Immunology and the Interdepartmental Immunobiology Center Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1544-2015","authenticated-orcid":false,"given":"Huan","family":"Xu","sequence":"additional","affiliation":[{"name":"Neurology Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1867-5634","authenticated-orcid":false,"given":"Andrew P.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Microbiology\u2010Immunology and the Interdepartmental Immunobiology Center Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9433-5017","authenticated-orcid":false,"given":"Priyam A.","family":"Patel","sequence":"additional","affiliation":[{"name":"Quantitative Data Science Core Center for Genetic Medicine Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5510-231X","authenticated-orcid":false,"given":"Yanan","family":"Chen","sequence":"additional","affiliation":[{"name":"Neurology Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7858-0170","authenticated-orcid":false,"given":"Damiano","family":"Fantini","sequence":"additional","affiliation":[{"name":"Urology Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Eaton","sequence":"additional","affiliation":[{"name":"Department of Microbiology\u2010Immunology and the Interdepartmental Immunobiology Center Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8520-7240","authenticated-orcid":false,"given":"Molly","family":"Karl","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology The George Washington University School of Medicine and Health Sciences  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2916-5752","authenticated-orcid":false,"given":"Eric D.","family":"Garrison","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology The George Washington University School of Medicine and Health Sciences  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0491-1269","authenticated-orcid":false,"given":"Indigo V. 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