{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T22:25:31Z","timestamp":1785536731184,"version":"3.56.0"},"reference-count":95,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>Type-II diabetes mellitus (T2DM) is a major risk factor for cognitive impairment. Protecting the brain environment against inflammation, and neurodegeneration, as well as preservation of the BBB veracity through modulating the crosstalk between insulin\/AKT\/GSK-3\u03b2 and Wnt\/\u03b2-catenin signaling, might introduce novel therapeutic targets.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Purpose<\/jats:title><jats:p>This study aimed at exploring the possible neuroprotective potential of vitamin D3 (VitD) and\/or rosuvastatin (RSV) in T2DM-induced cognitive deficits.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Methods<\/jats:title><jats:p>T2DM was induced by a high-fat sucrose diet and a single streptozotocin (STZ) dose. Diabetic rats were allocated into a diabetic control and three groups treated with RSV (15 mg\/kg\/day, PO), VitD (500 IU\/kg\/day, PO), or their combination.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Results<\/jats:title><jats:p>Administration of VitD and\/or RSV mitigated T2DM-induced metabolic abnormalities and restored the balance between the anti-inflammatory, IL 27 and the proinflammatory, IL 23 levels in the hippocampus. In addition, they markedly activated both the canonical and noncanonical Wnt\/\u03b2-catenin cassettes with stimulation of their downstream molecular targets. VitD and\/or RSV upregulated insulin and \u03b17 nicotinic acetylcholine (\u03b17nACh) receptors gene expression, as well as blood-brain barrier integrity markers including Annexin A1, claudin 3, and VE-cadherin. Also, they obliterated hippocampal ApoE-4 content, Tau hyperphosphorylation, and A\u03b2 deposition. These biochemical changes were reflected as improved behavioral performance in Morris water maze and novel object recognition tests and restored hippocampal histological profile.<\/jats:p><\/jats:sec><jats:sec id=\"sec005\"><jats:title>Conclusion<\/jats:title><jats:p>The current findings have accentuated the neuroprotective potential of VitD and RSV and provide new incentives to expand their use in T2DM-induced cognitive and memory decline. This study also suggests a superior benefit of combining both treatments over either drug alone.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0277457","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T18:24:01Z","timestamp":1668450241000},"page":"e0277457","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Vitamin D and rosuvastatin alleviate type-II diabetes-induced cognitive dysfunction by modulating neuroinflammation and canonical\/noncanonical Wnt\/\u03b2-catenin signaling"],"prefix":"10.1371","volume":"17","author":[{"given":"Muhammad","family":"Muneeb","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9235-7351","authenticated-orcid":true,"given":"Suzan M.","family":"Mansou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira","family":"Saleh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reham A.","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"pone.0277457.ref001","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1212\/WNL.53.9.1937","article-title":"Diabetes mellitus and the risk of dementia: The Rotterdam Study","volume":"53","author":"A Ott","year":"1999","journal-title":"Neurology"},{"key":"pone.0277457.ref002","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/nyas.12807","article-title":"Impact of diabetes on cognitive function and brain structure","volume":"1353","author":"A Moheet","year":"2015","journal-title":"Ann N Y Acad Sci"},{"key":"pone.0277457.ref003","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s11910-007-0058-7","article-title":"Type 2 diabetes and risk of cognitive impairment and dementia","author":"RA Whitmer","year":"2007","journal-title":"Current Neurology and Neuroscience Reports"},{"key":"pone.0277457.ref004","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/272827a0","article-title":"Insulin receptors are widely distributed in the central nervous system of the rat","volume":"272","author":"J Havrankova","year":"1978","journal-title":"Nature"},{"key":"pone.0277457.ref005","first-page":"34893","article-title":"Brain insulin receptors and spatial memory. 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