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No efficient therapy is available at present to combat such insults, and hence, novel safe and effective alternatives for MS therapy are extremely required. Rutin (RUT) is a flavonoid that exhibits antioxidant, anti-inflammatory, and neuroprotective effects in several brain injuries. The present study evaluated the potential beneficial effects of two doses of RUT in a model of pattern-III lesion of MS, in comparison to the conventional standard drug; dimethyl fumarate (DMF). Demyelination was induced in in male adult C57BL\/6 mice by dietary 0.2% (w\/w) cuprizone (CPZ) feeding for 6 consecutive weeks. Treated groups received either oral RUT (50 or 100\u00a0mg\/kg) or DMF (15\u00a0mg\/kg), along with CPZ feeding, for 6 consecutive weeks. Mice were then tested for behavioral changes, followed by biochemical analyses and histological examinations of the corpus callosum (CC). Results revealed that CPZ caused motor dysfunction, demyelination, and glial activation in demyelinated lesions, as well as significant oxidative stress, and proinflammatory cytokine elevation. Six weeks of RUT treatment significantly improved locomotor activity and motor coordination. Moreover, RUT considerably improved remyelination in the CC of CPZ\u2009+\u2009RUT-treated mice, as revealed by luxol fast blue staining and transmission electron microscopy. Rutin also significantly attenuated CPZ-induced oxidative stress and inflammation in the CC of tested animals. The effect of RUT100 was obviously more marked than either that of DMF, regarding most of the tested parameters, or even its smaller tested dose. In silico docking revealed that RUT binds tightly within NF-\u03baB at the binding site of the protein-DNA complex, with a good negative\n                    <jats:italic>score<\/jats:italic>\n                    of \u22126.79\u00a0kcal\/mol. Also, RUT-Kelch-like ECH-associated protein 1 (Keap1) model clarifies the possible inhibition of Keap1\u2013Nrf2 protein\u2013protein interaction. Findings of the current study provide evidence for the protective effect of RUT in CPZ-induced demyelination and behavioral dysfunction in mice, possibly by modulating NF-\u03baB and Nrf2 signaling pathways. The present study may be one of the first to indicate a pro-remyelinating effect for RUT, which might represent a potential additive benefit in treating MS.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s10787-024-01442-x","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T05:01:31Z","timestamp":1710997291000},"page":"1295-1315","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Neuroprotective effects of rutin against cuprizone-induced multiple sclerosis in mice"],"prefix":"10.1007","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8612-640X","authenticated-orcid":false,"given":"Mariam A.","family":"Nicola","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8481-2687","authenticated-orcid":false,"given":"Abdelraheim H.","family":"Attaai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud H.","family":"Abdel-Raheem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4005-982X","authenticated-orcid":false,"given":"Anber F.","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin F.","family":"Abu-Elhassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,21]]},"reference":[{"key":"1442_CR1","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.1007\/s10753-021-01447-6","volume":"44","author":"AE Abd El Aziz","year":"2021","unstructured":"Abd El Aziz AE, Sayed RH, Sallam NA et al (2021) Neuroprotective effects of telmisartan and nifedipine against cuprizone-induced demyelination and behavioral dysfunction in mice: roles of NF-\u03baB and Nrf2. 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