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Even though the pathogenesis of disease evolution is still obscure, accumulating evidence indicates that mitochondrial dysfunction plays a causative role in neurodegeneration and axonopathy in progressive MS patients. Here, we investigated the effects of dexpramipexole, a compound with a good safety profile in humans and able to sustain mitochondria functioning and energy production, in a mouse model of progressive MS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Female non\u2010obese diabetic mice were immunized with MOG<jats:sub>35\u201355<\/jats:sub>. Functional, immune and neuropathological parameters were analysed during disease evolution in animals treated or not with dexpramipexole. The compound's effects on bioenergetics and neuroprotection were also evaluated in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We found that oral treatment with dexpramipexole at a dose consistent with that well tolerated in humans delayed disability progression, extended survival, counteracted reduction of spinal cord mitochondrial DNA content and reduced spinal cord axonal loss of mice. Accordingly, the drug sustained in vitro bioenergetics of mouse optic nerve and dorsal root ganglia and counteracted neurodegeneration of organotypic mouse cortical cultures exposed to the adenosine triphosphate\u2010depleting agents oligomycin or veratridine. Dexpramipexole, however, was unable to affect the adaptive and innate immune responses both in vivo and in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implication<\/jats:title><jats:p>The present findings corroborate the hypothesis that neuroprotective agents may be of relevance to counteract MS progression and disclose the translational potential of dexpramipexole to treatment of progressive MS patients as a stand\u2010alone or adjunctive therapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15058","type":"journal-article","created":{"date-parts":[[2020,3,21]],"date-time":"2020-03-21T19:44:20Z","timestamp":1584819860000},"page":"3342-3356","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Neuroprotection induced by dexpramipexole delays disease progression in a mouse model of progressive multiple sclerosis"],"prefix":"10.1111","volume":"177","author":[{"given":"Daniela","family":"Buonvicino","sequence":"first","affiliation":[{"name":"Department of Health Sciences, Section of Clinical Pharmacology and Oncology University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Ranieri","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Section of Clinical Pharmacology and Oncology University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Pratesi","sequence":"additional","affiliation":[{"name":"Centre of Immunological Research DENOTHE, Department of Experimental and Clinical Medicine University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Gerace","sequence":"additional","affiliation":[{"name":"Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NeuroFarBa) University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Muzzi","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Section of Clinical Pharmacology and Oncology University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Guasti","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Research Unit of Histology &amp; Embryology University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Tofani","sequence":"additional","affiliation":[{"name":"Clinical Trials Coordinating Center of Istituto Toscano Tumori Azienda Ospedaliero\u2010Universitaria Careggi  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Chiarugi","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Section of Clinical Pharmacology and Oncology University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.114.095661"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2012.01.046"},{"issue":"1","key":"e_1_2_11_4_1","first-page":"S1","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Introduction and other protein targets","volume":"176","author":"Alexander S. 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