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.

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