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In this study, we evaluated the peripheral and central effects of clemastine on cognitive impairment induced by UC using an acetic acid (1\u00a0ml, 4% v\/v) model with emphasis on the role of PI3K\/Akt\/GSK-3\u03b2 signaling, ferroptosis, and autophagy in its possible mediated neuroprotection. Clemastine revealed a dose-dependent improvement of colonic damage linked with UC, as demonstrated by inhibition of TNF-\u03b1, IL-1\u03b2, and caspase-3 levels along with upregulation of claudin-1 expression. Importantly, the preservation of gut membrane integrity was associated with amelioration of UC-induced systemic inflammation together with restoration of PI3K\/Akt\/GSK-3\u03b2 signaling in the brain. Additionally, the neuroprotective actions of clemastine included the prevention of neuronal injury and death as evidenced by inhibition of oxidative stress markers and microglial activation (Iba-1 expression), which could exacerbate the neuroinflammatory response. Concurrently, inhibition of the pathological autophagic dysfunction and ferroptosis profile by clemastine, as clarified by LC3-II downregulation and LC3-I and GPX4 upregulation, led to behavioral and cognitive improvements, which were proven by decreased levels of A\u03b2 and tau protein. Importantly, by crossing the BBB, clemastine could exert additional anti-inflammatory and neuroprotective effects by affecting the central assessed pathways. In conclusion, these findings clarify the pivotal role of clemastine in the management of colonic inflammation-associated cognitive decline through modulating multiple and interacting peripheral and central pathways to provide its potent neuroprotection.<\/jats:p>","DOI":"10.1007\/s10787-026-02303-5","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T06:59:04Z","timestamp":1782802744000},"page":"5603-5618","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clemastine ameliorates ulcerative colitis-induced cognitive impairment by restoring PI3K\/Akt\/GSK-3\u03b2 signaling and suppressing ferroptosis"],"prefix":"10.1007","volume":"34","author":[{"given":"Manar A.","family":"Didamoony","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5221-4666","authenticated-orcid":false,"given":"Mustafa M.","family":"Shokr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem M.","family":"Eladawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamiaa A.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"2303_CR1","doi-asserted-by":"publisher","first-page":"110229","DOI":"10.1016\/j.abb.2024.110229","volume":"763","author":"M Abdelnaser","year":"2025","unstructured":"Abdelnaser M, Attya ME, El-Rehany MA, Fathy M (2025) Clemastine mitigates sepsis-induced acute kidney injury in rats; the role of \u03b1-Klotho\/TLR-4\/MYD-88\/NF-\u03baB\/Caspase-3\/p-P38 MAPK signaling pathways. 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