Cerebral hypoperfusion is a common feature of cerebral small vascular disease (CSVD), which has been considered as one of the causes of cognitive decline in recent years. Epimedium flavonoids (EF) are the main ingredients extracted from Epimedium. The purpose of this study was to investigate the effects of EF on cognitive impairment, and the underlying mechanisms in rats with permanent occlusion of the bilateral common carotid artery (2VO). EF (50, 100, and 200 mg/kg) was intragastrically administered for 12 weeks starting 2 weeks after 2VO surgery. The results showed that EF treatment improved learning and memory impairment in 2VO rats evaluated by novel object recognition and Y-maze tests. NeuN immunohistochemical staining indicated that EF alleviated neuronal loss in the hippocampus and cerebral cortex of 2VO rats. MAP-2 immunofluorescence staining and western blotting showed that EF protected neuronal dendrites and increased the expression of cytoskeleton proteins MAP-2 and NF200 in the hippocampus of 2VO rats. Moreover, EF protected the synapse ultrastructure detected by transmission electron microscopy, and increased the expression of synaptic plasticity-related proteins, including synaptophysin, synaptotagmin-I, synapsin I, PSD-95, p-NMDA2B, and p-CaMKII-α in the hippocampus of 2VO rats. In addition, EF increased the expression of neuregulin-1 (NRG-1), p-ErbB4, brain-derived neurotrophic factor (BDNF), p-Fyn, PI3K, p-Akt, and p-CREB in the hippocampus of 2VO rats. These results suggest that EF may protect neurons and synapses by activating the NRG1/ErbB4, BDNF/Fyn, and P13 K/Akt/CREB pathways in the hippocampus and cerebral cortex, thus improving cognitive impairment induced by chronic cerebral hypoperfusion. EF may be a potential candidate drug for chronic cerebral hypoperfusion and CSVD therapy.

脑低灌注是脑小血管病（CSVD）的共同特征，近年来被认为是导致认知能力下降的原因之一。淫羊藿黄酮（EF）是从淫羊藿中提取的主要成分。本研究的目的是研究 EF 对认知障碍的影响，以及双侧颈总动脉 (2VO) 永久性闭塞大鼠的潜在机制。EF（50、100 和 200 mg/kg）在 2VO 手术后 2 周开始胃内给药 12 周。结果表明，EF 治疗改善了通过新物体识别和 Y 迷宫测试评估的 2VO 大鼠的学习和记忆障碍。NeuN 免疫组织化学染色表明 EF 减轻了 2VO 大鼠海马和大脑皮层的神经元丢失。MAP-2免疫荧光染色和蛋白质印迹表明EF保护神经元树突并增加2VO大鼠海马中细胞骨架蛋白MAP-2和NF200的表达。此外，EF 保护了透射电子显微镜检测到的突触超微结构，并增加了突触可塑性相关蛋白的表达，包括突触素、突触结合蛋白-I、突触素 I、PSD-95、p-NMDA2B 和 p-CaMKII-α。 2VO 大鼠的海马体。此外，EF增加了2VO大鼠海马中neuregulin-1（NRG-1）、p-ErbB4、脑源性神经营养因子（BDNF）、p-Fyn、PI3K、p-Akt和p-CREB的表达. 这些结果表明 EF 可能通过激活海马和大脑皮层中的 NRG1/ErbB4、BDNF/Fyn 和 P13 K/Akt/CREB ​​通路来保护神经元和突触，从而改善慢性脑灌注不足引起的认知障碍。EF 可能是慢性脑灌注不足和 CSVD 治疗的潜在候选药物。