{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:31:54Z","timestamp":1784169114284,"version":"3.55.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Multiple sclerosis (MS) affects 2.8\u202fmillion people worldwide. Although the cause is unknown, various risk factors might be involved. MS involves the immune system attacking the central nervous system\u2019s myelin sheath, leading to neuron damage. This study used a cuprizone (CPZ)-intoxicated mouse model to simulate MS\u2019s demyelination\/remyelination process. It evaluated the molecular, histological, and behavioral effects of vanillic acid (VA), a natural phenolic acid, alone and with Ibudilast (IBD), a clinically tested MS medication. Mice were divided into a control group (regular chow) and a CPZ group (0.3% cuprizone chow for 5 consecutive weeks). During remyelination, the CPZ group was split into four groups: no therapy, 10\u202fmg\/kg of IBD, 30\u202fmg\/kg of VA, and combined, each treated for 4\u202fweeks. Behavioral, biochemical, molecular, and histopathological tests occurred in the 5<jats:sup>th<\/jats:sup> week (demyelination), 7<jats:sup>th<\/jats:sup> (early remyelination), and 9<jats:sup>th<\/jats:sup> (late remyelination). Cognitive assessments were at weeks 5 and 9. VA enhanced motor, coordination, and cognitive impairments in CPZ-intoxicated mice and improved histopathological, molecular, and biochemical features during early remyelination. IBD improved behavioral abnormalities across all tests, but combined therapy showed no significant difference from single therapies. Further investigations are necessary to understand VA\u2019s mechanisms and potential as an MS treatment.<\/jats:p>","DOI":"10.3389\/fnmol.2024.1503396","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T06:13:05Z","timestamp":1736489585000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Neurotherapeutic impact of vanillic acid and ibudilast on the cuprizone model of multiple sclerosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Rasha M.","family":"Alderbi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Z.","family":"Alam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Badrah S.","family":"Alghamdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadeil M.","family":"Alsufiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gamal S.","family":"Abd El-Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulfat M.","family":"Omar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam A.","family":"Al-Ghamdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"103618","DOI":"10.1016\/j.msard.2022.103618","article-title":"Anti-inflammatory compounds ameliorate locomotion and anxiety behaviors in Cuprizone mouse model of multiple sclerosis","volume":"59","author":"Alderbi","year":"2022","journal-title":"Mult. 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Food Chem."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3390\/brainsci14010012","article-title":"Vanillic acid ameliorates demyelination in a Cuprizone-induced multiple sclerosis rat model: possible underlying mechanisms","volume":"14","author":"Safwat","year":"2024","journal-title":"Brain Sci."},{"key":"ref38","first-page":"3053","article-title":"An overview of therapeutic effects of vanillic acid","volume":"20","author":"Sharma","year":"2020","journal-title":"Plant Arch."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"667511","DOI":"10.3389\/fneur.2021.667511","article-title":"Behavioral assessment of sensory, motor, emotion, and cognition in rodent models of intracerebral hemorrhage","volume":"12","author":"Shi","year":"2021","journal-title":"Front. 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Suppl."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1146\/annurev.med.53.082901.103952","article-title":"Cyclooxygenase-2: a therapeutic target","volume":"53","author":"Turini","year":"2002","journal-title":"Annu. Rev. Med."},{"key":"ref9005","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22010361","article-title":"Vanillic Acid, a Bioactive Phenolic Compound, Counteracts LPS-Induced Neurotoxicity by Regulating c-Jun N-Terminal Kinase in Mouse Brain","volume":"22","author":"Ullah","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.jneuroim.2005.07.004","article-title":"Role of interleukin 4 in Spanish multiple sclerosis patients","volume":"168","author":"Urcelay","year":"2005","journal-title":"J. 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