Vascular dementia (VD) is the second most common dementia disease after Alzheimer’s diseases (AD) in the world. Donepezil is used to treat mild to moderate AD, and it has been shown to treat cognitive impairment and memory deficits caused by VD. However, the action mechanism of donepezil against VD has not been clarified. In this study, a bilateral common carotid artery occlusion (BCCAO) model was established in rats to simulate the pathology of VD. Two weeks after the surgery, the rats were administered donepezil (10 mg · kg⁻¹ · d⁻¹, ig) for 3 weeks, and then subjected to behavioral tests. We showed that donepezil treatment significantly improved the performance of BCCAO rats in Morris Water Mazes test and Step-down test. Furthermore, we showed that donepezil treatment significantly attenuated neurodegeneration and restored the synapse dendritic spines density in cortex and hippocampus. We revealed that donepezil treatment significantly increased BDNF expression in cortex and hippocampus. Interestingly, donepezil treatment significantly decreased nuclear translocation of HDAC6 and the binding between HDAC6 and BDNF promoter IV in cortex, but not in the hippocampus. The attenuated neurodegeneration by donepezil in cortex and hippocampus might due to the reduced ROS levels and increased phosphorylation of AMPK, whereas increased phosphorylation of AKT was only detected in cortex. In conclusion, our results demonstrate that donepezil attenuates neurodegeneration in cortex and hippocampus via increasing BDNF expression; the regulation of donepezil on HDAC6 occurred in cortex, but not in the hippocampus. This study further clarifies the pharmacological mechanism of donepezil, while also emphasizes the promising epigenetic regulation of HDAC6.

血管性痴呆（VD）是世界上仅次于阿尔茨海默病（AD）的第二大常见痴呆症。多奈哌齐用于治疗轻度至中度 AD，并且已被证明可治疗由 VD 引起的认知障碍和记忆障碍。然而，多奈哌齐对VD的作用机制尚未阐明。本研究建立大鼠双侧颈总动脉闭塞（BCCAO）模型，模拟VD病理。手术后两周，给大鼠服用多奈哌齐（10 mg·kg ^-1  ·d ^-1, ig) 3 周，然后进行行为测试。我们发现多奈哌齐治疗显着改善了 BCCAO 大鼠在莫里斯水迷宫试验和降压试验中的表现。此外，我们发现多奈哌齐治疗显着减轻神经变性并恢复皮质和海马中的突触树突棘密度。我们发现多奈哌齐治疗显着增加了皮质和海马中的 BDNF 表达。有趣的是，多奈哌齐治疗显着降低了皮质中 HDAC6 的核转位以及 HDAC6 和 BDNF 启动子 IV 之间的结合，但在海马中没有。多奈哌齐对皮质和海马的神经变性减弱可能是由于 ROS 水平降低和 AMPK 磷酸化增加，而仅在皮质中检测到增加的 AKT 磷酸化。总之，我们的研究结果表明，多奈哌齐通过增加 BDNF 表达来减轻皮质和海马的神经退行性变。多奈哌齐对HDAC6的调节发生在皮层，但不在海马中。本研究进一步阐明了多奈哌齐的药理作用机制，同时也强调了HDAC6的表观遗传调控前景。