Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Biology, School of Pharmacy, Newgiza University, First 6th of October, Giza 3296121, Egypt.
Int Immunopharmacol. 2023 Mar;116:109841. doi: 10.1016/j.intimp.2023.109841. Epub 2023 Feb 8.
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.
溃疡性结肠炎（UC）是一种持续性炎症性肠病（IBD），被认为是认知障碍的危险因素。多奈哌齐（DON）是一种中枢作用的乙酰胆碱酯酶抑制剂（AChEI），被批准用于治疗阿尔茨海默病（AD）。我们旨在研究 DON 对乙酸（AA）诱导的大鼠 UC 的影响，并评估其在该模型中减轻炎症反应、氧化应激和细胞凋亡的能力及其相关的认知缺陷。大鼠分为：正常组、DON 组、AA 组和 AA+DON 组。DON（5mg/kg/天）口服给药，连续 14 天，或在 UC 诱导当天开始给药。通过单次直肠内注射 1ml4%乙酸来诱发结肠炎。结果表明，DON 可显著改善行为异常，减轻炎症、细胞凋亡和海马组织病理学变化。此外，DON 显著缓解了与结肠炎相关的宏观和微观变化。有趣的是，DON 通过抑制 AA 诱导的核因子 kappa-B（NF-κB）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）的激活，抑制了促炎细胞因子的产生，同时抑制了血清 IL-1β。DON 抑制了结肠脂质过氧化，恢复了抗氧化剂，显著改善了中性粒细胞浸润程度，并抑制了结肠炎诱导的基质金属蛋白酶-9（MMP-9）的产生。此外，DON 降低了 Bax/Bcl-2 比值和 caspase-3 蛋白表达。最终，在脂多糖（LPS）处理的 RAW 264.7 巨噬细胞中，DON 抑制了一氧化氮（NO）的释放，表明 DON 具有显著抑制免疫细胞炎症的能力。综上所述，DON 通过其抗氧化作用和调节促炎细胞因子和细胞凋亡，改善了实验性结肠炎及其相关的认知功能障碍。因此，DON 可能是 UC 和相关神经紊乱的治疗候选药物。
