Clemastine ameliorates ulcerative colitis-induced cognitive impairment by restoring PI3K/Akt/GSK-3β signaling and suppressing ferroptosis.

Ulcerative colitis (UC) is a refractory inflammatory bowel disease with ongoing colonic inflammation and extra-intestinal manifestations, including cognitive impairment. In this study, we evaluated the peripheral and central effects of clemastine on cognitive impairment induced by UC using an acetic acid (1 ml, 4% v/v) model with emphasis on the role of PI3K/Akt/GSK-3β 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-α, IL-1β, 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-3β 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 Aβ 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.