Vascular dementia (VaD), caused by stroke or small vessel disease, is the second‐most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris water maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Aβ1‐42 in BCCAO rats by enzyme‐linked immunosorbent assay. Post‐translational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlights the importance of PTMs in neurodegenerative diseases. In this study, we used western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2‐hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl‐PTMs.

中文翻译：

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多奈哌齐下调双侧颈总动脉闭塞诱导的血管性痴呆大鼠大脑中的丙酰化、2-羟基异丁酰化、丁酰化、琥珀酰化和巴豆酰化。


血管性痴呆（VaD）由中风或小血管疾病引起，是继阿尔茨海默病（AD）之后第二常见的痴呆类型。多奈哌齐是一种乙酰胆碱酯酶抑制剂，目前用于轻度至中度 AD 患者，最近被证明可以改善 VaD 患者的认知能力。在这项研究中，我们评估了多奈哌齐对 VaD 的影响，并研究了潜在的分子作用机制。 VaD 是通过结扎双侧颈总动脉闭塞 (BCCAO) 建立的。通过莫里斯水迷宫（MWM）测试和注意力转移任务（ASST）测试执行功能。我们的结果表明，多奈哌齐改善了 BCCAO 大鼠的执行功能障碍和认知灵活性。此外，我们通过酶联免疫吸附测定表明，多奈哌齐治疗降低了 BCCAO 大鼠的 Aβ1-42 水平。众所周知，翻译后修饰（PTM）是调节各种细胞过程的关键机制。此外，PTM 与中枢神经系统有关，这凸显了 PTM 在神经退行性疾病中的重要性。在这项研究中，我们使用蛋白质印迹分析来鉴定接受或不接受多奈哌齐治疗的 BCCAO 大鼠海马中的几种新的 PTM。数据显示，与假手术大鼠相比，BCCAO 大鼠海马中的赖氨酸丙酰化、2-羟基异丁酰化、丁酰化、琥珀酰化和巴豆酰化升高。这种增加被多奈哌齐治疗消除。综上所述，我们推测多奈哌齐治疗可能通过减少异常的酰基-PTM 来改善 VaD 动物模型的认知功能。