Donepezil halts acetic acid-induced experimental colitis in rats and its associated cognitive impairment through regulating inflammatory/oxidative/apoptotic cascades: An add-on to its anti-dementia activity

Abstract

Ulcerative colitis (UC) is a persistent inflammatory bowel disease (IBD) that is regarded as a risk factor for cognitive impairment. Donepezil (DON), a centrally acting acetylcholinesterase inhibitor (AChEI), is approved for the management of Alzheimer's disease (AD). We aimed to scrutinize the impact of DON on acetic acid (AA)-induced UC in rats and to evaluate its ability to attenuate inflammatory response, oxidative strain, and apoptosis in this model and its associated cognitive deficits. Rats were categorized into: normal, DON, AA, and AA + DON groups. DON (5 mg/kg/day) was administered orally for 14 days either alone or beginning with the day of UC induction. Colitis was evoked by a single transrectal injection of 1 ml of 4 % acetic acid. Results revealed that DON significantly improved the behavioral abnormalities with the mitigation of inflammation, apoptosis, and histopathological changes in the hippocampi of the colitis group. Moreover, DON significantly alleviated the macroscopic and microscopic changes associated with colitis. Interestingly, DON inhibited pro-inflammatory cytokines via suppression of AA-induced activation of nuclear factor kappa-B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) in the colon, along with serum IL-1β. DON inhibited colon lipid peroxidation, restored the antioxidants with a significant amelioration of the degree of neutrophil infiltration, and repressed colitis-induced matrix metalloproteinases-9 (MMP-9) production. Furthermore, DON decreased the Bax/Bcl-2 ratio and caspase-3 protein expressions. Eventually, in lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells, DON suppressed nitric oxide (NO) release, demonstrating the ability of DON to significantly curtail inflammation in immune cells. Taken together, DON ameliorated experimental colitis and its linked cognitive dysfunction, possibly via its antioxidant effect and modulation of pro-inflammatory cytokines and apoptosis. Thereby, DON could be a therapeutic nominee for UC and associated neurological disorders.