{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:39:02Z","timestamp":1792510742527,"version":"4.5.0"},"reference-count":82,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Cortical grey matter pathology manifests early demyelinating diseases and is a primary driver of permanent neurological impairment. Our study investigated the neuroprotective effects of betaine against cuprizone (CPZ)\u2010induced damage to the cerebral cortex in rats, focusing on its ability to modulate the upstream WNT4\/mTOR signalling pathway. Cortical tissues were collected for biochemical assessments of oxidative and inflammatory markers, real\u2010time PCR analysis for\n                    <jats:italic>WNT4<\/jats:italic>\n                    ,\n                    <jats:italic>GFAP<\/jats:italic>\n                    , and\n                    <jats:italic>mTOR<\/jats:italic>\n                    gene expressions, histopathological examination, and immunohistochemical analysis of vimentin, S100, and synaptophysin. Exposure to CPZ resulted in severe cortical damage with profound oxidative stress. This oxidative status triggered a pronounced neuroinflammatory response, leading to elevated levels of IL\u201017A, IL\u20101\u03b2, and TNF\u2010\u03b1, which in turn caused chronic, hyper\u2010reactive astrogliosis. This was confirmed by the upregulation of\n                    <jats:italic>GFAP<\/jats:italic>\n                    gene expression and enhanced immunohistochemical staining of vimentin and S100\u03b2, resulting in extensive loss of cortical synaptic integrity (depletion of synaptophysin). Importantly, treatment with betaine served as a molecular brake, significantly downregulating the aberrant gene expressions of\n                    <jats:italic>WNT4<\/jats:italic>\n                    and\n                    <jats:italic>mTOR<\/jats:italic>\n                    . This targeted downregulation effectively reduced the overactive glial response, leading to a significant reduction in astrogliosis (\n                    <jats:italic>GFAP<\/jats:italic>\n                    , vimentin, and S100\u03b2), alleviated the pro\u2010inflammatory cytokines, restored endogenous antioxidant functions, and ultimately preserved cortical synaptophysin expression and cellular structure. Overall, these results demonstrate that betaine exerts a neuroprotective effect against CPZ\u2010induced cortical injury, which is strongly associated with the attenuation of WNT4\/mTOR signalling pathway hyperactivation, suppression of astrogliosis, and preservation of synaptic density. The preservation of cortical grey matter integrity is directly associated with alleviating cognitive deficits and long\u2010term physical disabilities in multiple sclerosis patients, emphasising the translational relevance of targetable neuroprotective therapies.\n                  <\/jats:p>","DOI":"10.1002\/jbt.71138","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:49:14Z","timestamp":1792507754000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Betaine Attenuates Cuprizone\u2010Induced Cortical Demyelination: The Role of the WNT4\/mTOR Signalling Pathway in Regulating Astrogliosis and Synaptic Integrity"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1458-5525","authenticated-orcid":false,"given":"Yara M.","family":"Said","sequence":"first","affiliation":[{"name":"Euro\u2010Mediterranean Master in Neuroscience and Biotechnology, Faculty of Science Alexandria University Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2078-1193","authenticated-orcid":false,"given":"Heba\u2010Tallah Abd Elrahim","family":"Abd Elkader","sequence":"additional","affiliation":[{"name":"Zoology, Biological and Geological Sciences Department, Faculty of Education Alexandria University Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gihad Jamal","family":"Bekheet","sequence":"additional","affiliation":[{"name":"Euro\u2010Mediterranean Master in Neuroscience and Biotechnology, Faculty of Science Alexandria University Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3269-7458","authenticated-orcid":false,"given":"Sherine","family":"Abdel Salam","sequence":"additional","affiliation":[{"name":"Zoology Department, Faculty of Science Alexandria University Alexandria Egypt"},{"name":"Department of Biological Sciences, Faculty of Science King Faisal University Al\u2010Ahsa Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9885-6250","authenticated-orcid":false,"given":"Amina E.","family":"Essawy","sequence":"additional","affiliation":[{"name":"Zoology Department, Faculty of Science Alexandria University Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2012.168"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxrep.2025.101974"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2014.09.003"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-022-00956-6"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000768"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh641"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(08)70191-1"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21906"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab132"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2020.102335"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03116"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pathophys.2018.04.004"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.04.173"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/7191080"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-025-01603-z"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-024-00823-z"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.306064"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a020420"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9040843"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcot.2022.101760"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.12.001"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2020.106282"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4103-08.2009"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.06.055"},{"issue":"1","key":"e_1_2_10_26_1","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.3389\/fneur.2020.01028","article-title":"Tuberous Sclerosis Complex as Disease Model for Investigating Mtor\u2010Related Gliopathy During Epileptogenesis","volume":"11","author":"Zimmer T. 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