{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:02:00Z","timestamp":1785412920178,"version":"3.56.0"},"reference-count":45,"publisher":"IMR Press","issue":"7","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Background:The cuprizone (CPZ) model has been used to study de- and re-myelination in mice; Previous studies have used different routes for CPZ intoxication, but the results were highly variable.Methods:Here, we compared demyelination induced by the administration of 0.3% CPZ mixed with ground rodent chow and a 400 mg\/kg CPZ suspension in carboxymethyl cellulose (CMC) via oral gavage in SWR\/J mice. The mice were assigned into a control group, a CPZ diet group, and an oral CPZ groups (n = 6 mice\/group). Rotarod, hanging wire, and open field tests were performed to evaluate locomotor activity. Histological analyses were conducted on the corpus callosum (CC) of the brain to determine myelin loss and on the liver to assess the toxicity of CPZ.Results:The administration of CPZ with ground rodent chow significantly reduced body weight gains, grip strength, and motor coordination performance during the 5-week demyelination period. In contrast, all analyzed parameters were less different in mice receiving CPZ via oral gavage. However, both CPZ routes significantly reduced myelin content in the CC. Additionally, the oral administration of CPZ had strong effects on liver toxicity compared to that of CPZ diet feeding. This study showed that both routes of CPZ intoxication could induce reproducible and consistent demyelination changes within the CC of the mouse brain, with the CPZ diet being more effective based on all analytical parameters and having fewer toxic effects on the liver compared with oral CPZ.Conclusions:In conclusion, the resultsassist in the selection of a suitable multiple sclerosis (MS) model for investigating disease mechanisms and therapies.<\/jats:p>","DOI":"10.31083\/jin52589","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:01:26Z","timestamp":1785409286000},"source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of the Behavioral and Histopathological Outcomes of Two Cuprizone Administration Routes in a Mouse Model of Multiple Sclerosis"],"prefix":"10.31083","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8104-5862","authenticated-orcid":true,"given":"Kholoud M.","family":"Al-Otaibi","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Al-Baha University, 65779 Al-Baha, Saudi Arabia"},{"name":"Neuroscience and Geroscience Research Unit, King Fahd Medical Research Center, King Abdulaziz University, 21589 Jeddah, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Wallin MT, Culpepper WJ, Nichols E, Bhutta ZA, Gebrehiwot TT, Hay SI, et al. Global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. Neurology. 2019; 18: 269\u2013285.","DOI":"10.1016\/S1474-4422(18)30443-5"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Browne P, Chandraratna D, Angood C, Tremlett H, Baker C, Taylor BV, et al. Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. Neurology. 2014; 83: 1022\u20131024.","DOI":"10.1212\/WNL.0000000000000768"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Thompson KK, Tsirka SE. Guanabenz modulates microglia and macrophages during demyelination. Scientific Reports. 2020; 10: 19333.","DOI":"10.1038\/s41598-020-76383-w"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Ghasemi N, Razavi S, Nikzad E. Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell Journal. 2017; 19: 1\u201310.","DOI":"10.22074\/cellj.2016.4867"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Compston A, Coles A. Multiple sclerosis. Lancet. 2008; 372: 1502\u20131517.","DOI":"10.1016\/S0140-6736(08)61620-7"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain. 2006; 129: 3165\u20133172.","DOI":"10.1093\/brain\/awl217"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Goldschmidt T, Antel J, K\u00f6nig FB, Br\u00fcck W, Kuhlmann T. Remyelination capacity of the MS brain decreases with disease chronicity. Neurology. 2009; 72: 1914\u20131921.","DOI":"10.1212\/WNL.0b013e3181a8260a"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Zhen W, Liu A, Lu J, Zhang W, Tattersall D, Wang J. An Alternative Cuprizone-Induced Demyelination and Remyelination Mouse Model. ASN Neuro. 2017; 9: 1759091417725174.","DOI":"10.1177\/1759091417725174"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Blakemore WF, Franklin RJM. Remyelination in experimental models of toxin-induced demyelination. Advances in multiple Sclerosis and Experimental Demyelinating Diseases In Advances in multiple Sclerosis and Experimental Demyelinating Diseases (pp. 193-212). Springer: Berlin, Heidelberg, Germany. 2008.","DOI":"10.1007\/978-3-540-73677-6_8"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Torre-Fuentes L, Moreno-Jim\u00e9nez L, Pytel V, Mat\u00edas-Guiu JA, G\u00f3mez-Pinedo U, Mat\u00edas-Guiu J. Experimental models of demyelination and remyelination. Neurologia (English Edition). 2020; 35: 32\u201339.","DOI":"10.1016\/j.nrl.2017.07.002"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Skripuletz T, Gudi V, Hackstette D, Stangel M. De- and remyelination in the CNS white and grey matter induced by cuprizone: the old, the new, and the unexpected. Histology and Histopathology. 2011; 26: 1585\u20131597.","DOI":"10.14670\/HH-26.1585"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Pfeifenbring S, Nessler S, Wegner C, Stadelmann C, Br\u00fcck W. Remyelination After Cuprizone-Induced Demyelination Is Accelerated in Juvenile Mice. Journal of Neuropathology and Experimental Neurology. 2015; 74: 756\u2013766.","DOI":"10.1097\/NEN.0000000000000214"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Gudi V, Gingele S, Skripuletz T, Stangel M. Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned. Frontiers in Cellular Neuroscience. 2014; 8: 73.","DOI":"10.3389\/fncel.2014.00073"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Hochstrasser T, Exner GL, Nyamoya S, Schmitz C, Kipp M. Cuprizone-Containing Pellets Are Less Potent to Induce Consistent Demyelination in the Corpus Callosum of C57BL\/6 Mice. Journal of Molecular Neuroscience. 2017; 61: 617\u2013624.","DOI":"10.1007\/s12031-017-0903-3"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Zatta P, Raso M, Zambenedetti P, Wittkowski W, Messori L, Piccioli F, et al. Copper and zinc dismetabolism in the mouse brain upon chronic cuprizone treatment. Cellular and Molecular Life Sciences : CMLS. 2005; 62: 1502\u20131513.","DOI":"10.1007\/s00018-005-5073-8"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Liu L, Belkadi A, Darnall L, Hu T, Drescher C, Cotleur AC, et al. CXCR2-positive neutrophils are essential for cuprizone-induced demyelination: relevance to multiple sclerosis. Nature Neuroscience. 2010; 13: 319\u2013326.","DOI":"10.1038\/nn.2491"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Al-Otaibi KM, Alghamdi BS, Al-Ghamdi MA, Mansouri RA, Ashraf GM, Omar UM. Therapeutic effect of combination vitamin D3 and siponimod on remyelination and modulate microglia activation in cuprizone mouse model of multiple sclerosis. Frontiers in Behavioral Neuroscience. 2023; 16: 1068736.","DOI":"10.3389\/fnbeh.2022.1068736"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Abo Taleb HA, Alghamdi BS. Neuroprotective Effects of Melatonin during Demyelination and Remyelination Stages in a Mouse Model of Multiple Sclerosis. Journal of Molecular Neuroscience. 2020; 70: 386\u2013402.","DOI":"10.1007\/s12031-019-01425-6"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Lan W, He L, Liu Y. Preparation and Properties of Sodium Carboxymethyl Cellulose\/Sodium Alginate\/Chitosan Composite Film. Coatings. 2018; 8: 291.","DOI":"10.3390\/coatings8080291"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Kopanitsa MV, Lehtim\u00e4ki KK, Forsman M, Suhonen A, Koponen J, Piiponniemi TO, et al. Cognitive disturbances in the cuprizone model of multiple sclerosis. Genes, Brain, and Behavior. 2021; 20: e12663.","DOI":"10.1111\/gbb.12663"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Han SR, Kang YH, Jeon H, Lee S, Park SJ, Song DY, et al. Differential Expression of miRNAs and Behavioral Change in the Cuprizone-Induced Demyelination Mouse Model. International Journal of Molecular Sciences. 2020; 21: 646.","DOI":"10.3390\/ijms21020646"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Balkaya M, Kr\u00f6ber JM, Rex A, Endres M. Assessing post-stroke behavior in mouse models of focal ischemia. Journal of Cerebral Blood Flow and Metabolism. 2013; 33: 330\u2013338.","DOI":"10.1038\/jcbfm.2012.185"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Mohamed-Fathy Kamal O, Ojeda-Hern\u00e1ndez DD, Selma-Calvo B, Benito-Mart\u00edn MS, Fuente-Mart\u00edn SDL, Garc\u00eda-Mart\u00edn M, et al. Technical Assessment of Motor and Behavioral Tests in Rodent Models of Multiple Sclerosis. Journal of Integrative Neuroscience. 2025; 24: 26429.","DOI":"10.31083\/JIN26429"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Sen MK, Almuslehi MSM, Coorssen JR, Mahns DA, Shortland PJ. Behavioural and histological changes in cuprizone-fed mice. Brain, Behavior, and Immunity. 2020; 87: 508\u2013523.","DOI":"10.1016\/j.bbi.2020.01.021"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Cardiff RD, Miller CH, Munn RJ. Manual hematoxylin and eosin staining of mouse tissue sections. Cold Spring Harbor Protocols. 2014; 2014: 655\u2013658.","DOI":"10.1101\/pdb.prot073411"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Groebe A, Clarner T, Baumgartner W, Dang J, Beyer C, Kipp M. Cuprizone treatment induces distinct demyelination, astrocytosis, and microglia cell invasion or proliferation in the mouse cerebellum. Cerebellum. 2009; 8: 163\u2013174.","DOI":"10.1007\/s12311-009-0099-3"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Blakemore WF. Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice. Journal of Neurocytology. 1972; 1: 413\u2013426.","DOI":"10.1007\/BF01102943"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Blakemore WF. Demyelination of the superior cerebellar peduncle in the mouse induced by cuprizone. Journal of the Neurological Sciences. 1973; 20: 63\u201372.","DOI":"10.1016\/0022-510x(73)90118-4"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Bruce CC, Zhao C, Franklin RJM. Remyelination - An effective means of neuroprotection. Hormones and Behavior. 2010; 57: 56\u201362.","DOI":"10.1016\/j.yhbeh.2009.06.004"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Franklin RJM. Why does remyelination fail in multiple sclerosis? Nature Reviews. Neuroscience. 2002; 3: 705\u2013714.","DOI":"10.1038\/nrn917"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Mojaverrostami S, Pasbakhsh P, Madadi S, Nekoonam S, Zarini D, Noori L, et al. Calorie restriction promotes remyelination in a Cuprizone-Induced demyelination mouse model of multiple sclerosis. Metabolic Brain Disease. 2020; 35: 1211\u20131224.","DOI":"10.1007\/s11011-020-00597-0"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Hiremath MM, Saito Y, Knapp GW, Ting JP, Suzuki K, Matsushima GK. Microglial\/macrophage accumulation during cuprizone-induced demyelination in C57BL\/6 mice. Journal of Neuroimmunology. 1998; 92: 38\u201349.","DOI":"10.1016\/s0165-5728(98)00168-4"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Hilton JBW, Kysenius K, Liddell JR, Mercer SW, Hare DJ, Buncic G, et al. Evidence for decreased copper associated with demyelination in the corpus callosum of cuprizone-treated mice. Metallomics: Integrated Biometal Science. 2024; 16: mfad072.","DOI":"10.1093\/mtomcs\/mfad072"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Chang H, Liu J, Zhang Y, Wang F, Wu Y, Zhang L, et al. Increased central dopaminergic activity might be involved in the behavioral abnormality of cuprizone exposure mice. Behavioural Brain Research. 2017; 331: 143\u2013150.","DOI":"10.1016\/j.bbr.2017.05.045"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Sukoff Rizzo SJ, Crawley JN. Behavioral Phenotyping Assays for Genetic Mouse Models of Neurodevelopmental, Neurodegenerative, and Psychiatric Disorders. Annual Review of Animal Biosciences. 2017; 5: 371\u2013389.","DOI":"10.1146\/annurev-animal-022516-022754"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Li Z, He Y, Fan S, Sun B. Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination. Neuroscience Bulletin. 2015; 31: 617\u2013625.","DOI":"10.1007\/s12264-015-1555-3"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Cui C, Wang J, Mullin AP, Caggiano AO, Parry TJ, Colburn RW, et al. The antibody rHIgM22 facilitates hippocampal remyelination and ameliorates memory deficits in the cuprizone mouse model of demyelination. Brain Research. 2018; 1694: 73\u201386.","DOI":"10.1016\/j.brainres.2018.05.013"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Yu H, Wu M, Lu G, Cao T, Chen N, Zhang Y, et al. Prednisone alleviates demyelination through regulation of the NLRP3 inflammasome in a C57BL\/6 mouse model of cuprizone-induced demyelination. Brain Research. 2018; 1678: 75\u201384.","DOI":"10.1016\/j.brainres.2017.09.034"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Elbaz EM, Senousy MA, El-Tanbouly DM, Sayed RH. Neuroprotective effect of linagliptin against cuprizone-induced demyelination and behavioural dysfunction in mice: A pivotal role of AMPK\/SIRT1 and JAK2\/STAT3\/NF-\u03baB signalling pathway modulation. Toxicology and Applied Pharmacology. 2018; 352: 153\u2013161.","DOI":"10.1016\/j.taap.2018.05.035"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Kumar P, Sharma G, Gupta V, Kaur R, Thakur K, Malik R, et al. Preclinical Explorative Assessment of Dimethyl Fumarate-Based Biocompatible Nanolipoidal Carriers for the Management of Multiple Sclerosis. ACS Chemical Neuroscience. 2018; 9: 1152\u20131158.","DOI":"10.1021\/acschemneuro.7b00519"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Wang WW, Lu L, Bao TH, Zhang HM, Yuan J, Miao W, et al. Scutellarin Alleviates Behavioral Deficits in a Mouse Model of Multiple Sclerosis, Possibly Through Protecting Neural Stem Cells. Journal of Molecular Neuroscience. 2016; 58: 210\u2013220.","DOI":"10.1007\/s12031-015-0660-0"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009; 132: 1175\u20131189.","DOI":"10.1093\/brain\/awp070"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Stys PK, Zamponi GW, van Minnen J, Geurts JJG. Will the real multiple sclerosis please stand up? Nature Reviews. Neuroscience. 2012; 13: 507\u2013514.","DOI":"10.1038\/nrn3275"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Franco-Pons N, Torrente M, Colomina MT, Vilella E. Behavioral deficits in the cuprizone-induced murine model of demyelination\/remyelination. Toxicology Letters. 2007; 169: 205\u2013213.","DOI":"10.1016\/j.toxlet.2007.01.010"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Hibbits N, Pannu R, Wu TJ, Armstrong RC. Cuprizone demyelination of the corpus callosum in mice correlates with altered social interaction and impaired bilateral sensorimotor coordination. ASN Neuro. 2009; 1: e00013.","DOI":"10.1042\/AN20090032"}],"container-title":["Journal of Integrative Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/25\/7\/10.31083\/JIN52589","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:01:39Z","timestamp":1785409299000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/25\/7\/10.31083\/JIN52589"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":45,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026]]}},"alternative-id":["S0219-6352(26)01167-8"],"URL":"https:\/\/doi.org\/10.31083\/jin52589","relation":{},"ISSN":["0219-6352","1757-448X"],"issn-type":[{"value":"0219-6352","type":"print"},{"value":"1757-448X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"article-number":"52589"}}