Chronic cerebral hypoperfusion is a common cause of cerebral small vascular disease (CSVD). White matter (WM) lesions are the typical pathological manifestation of CSVD and contribute to cognitive decline. Epimedium flavonoids (EF) are the main component in Epimedium brevicornu Maxim., which is commonly used in traditional Chinese medicine. The purpose of this study was to investigate the effects of EF on cognitive impairment and the underlying mechanisms in a CSVD rat model induced with chronic cerebral hypoperfusion. The model was established by permanent bilateral common carotid artery occlusion (2VO) in rats. EF (50, 100, and 200 mg/kg) was intragastrically administered once a day for 12 weeks starting 2 weeks after 2VO surgery. The learning and memory capacity of the rats were measured using the Morris water maze and step-through tests. WM lesions were observed by MRI-diffusion tensor imaging, transmission electron microscopy, and LFB staining. Oligodendrocytes were detected by immunohistochemistry. Western blotting assay was used to determine the level of protein expression. The results showed that EF significantly improved learning and memory impairment, alleviated WM nerve fiber injuries and demyelination, and increased the number of mature oligodendrocytes in the corpus callosum, subcortical WM, and periventricular WM in 2VO rats. Mechanistically, EF reduced the expression of Lingo-1 and ROCK2 and increased the levels of phosphorylated (p-) Fyn, brain-derived neurotrophic factor (BDNF), TrkB, neuregulin-1 (NRG-1), p-ErbB4, PI3K p85 and p110α, p-Akt, and p-CREB in the corpus callosum of 2VO rats. These results suggest that EF may improve cognitive impairment and WM lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/TrkB, NRG-1/ErbB4, and the downstream PI3K/Akt/CREB pathways in WM. Thus, EF can be used as a potential neuroprotective agent in CSVD therapy.

中文翻译：

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淫羊藿黄酮通过抑制Lingo-1/Fyn/ROCK通路和激活BDNF/NRG1/PI3K通路改善大鼠慢性脑灌注不足引起的认知障碍和白质病变。

慢性脑灌注不足是脑小血管病 (CSVD) 的常见原因。白质 (WM) 病变是 CSVD 的典型病理表现，会导致认知能力下降。淫羊藿黄酮类化合物（EF）是中药常用的淫羊藿中的主要成分。本研究的目的是研究 EF 对认知障碍的影响及其在慢性脑灌注不足诱导的 CSVD 大鼠模型中的潜在机制。通过大鼠双侧颈总动脉永久闭塞（2VO）建立模型。EF（50、100 和 200 mg/kg）在 2VO 手术后 2 周开始每天一次胃内给药，持续 12 周。使用Morris水迷宫和步进测试测量大鼠的学习和记忆能力。通过 MRI 扩散张量成像、透射电子显微镜和 LFB 染色观察 WM 病变。通过免疫组织化学检测少突胶质细胞。蛋白质印迹分析用于确定蛋白质表达水平。结果表明，EF显着改善了2VO大鼠的学习记忆障碍，减轻了WM神经纤维损伤和脱髓鞘，并增加了胼胝体、皮层下WM和脑室周围WM成熟少突胶质细胞的数量。从机制上讲，EF 降低了 Lingo-1 和 ROCK2 的表达并增加了磷酸化 (p-) Fyn、脑源性神经营养因子 (BDNF)、TrkB、neuregulin-1 (NRG-1)、p-ErbB4、PI3K p85 的水平2VO 大鼠胼胝体中的 p110α、p-Akt 和 p-CREB。这些结果表明，EF 可能通过抑制 Lingo-1/Fyn/ROCK 通路，激活 BDNF/TrkB、NRG-1/ErbB4 和下游 PI3K/Akt/CREB ​​通路来改善慢性脑灌注不足引起的认知障碍和 WM 病变。在 WM。因此，EF 可用作 CSVD 治疗中的潜在神经保护剂。