RAGE acted as a new anti-inflammatory target for Icariin’s treatment against vascular dementia based on network pharmacology-directed verification

Vascular dementia (VaD) ranks as the second most prevalent form of dementia and poses a considerable global health challenge. Icariin has been recognized for its robust neuroprotective effects in combating VaD. Nonetheless, the underlying mechanisms have not been fully elucidated. An integrated approach involving network pharmacology, molecular docking, and molecular dynamics simulations (MDS) was employed to systematically investigate the potential pharmacological actions of Icariin in counteracting VaD. The AGE/RAGE pathway was identified as a promising anti-inflammatory pathway. A chronic cerebral hypoperfusion mouse model was utilized to establish VaD. Both Icariin and FP S-ZM1 (a RAGE inhibitor) were administered through oral gavage and intraperitoneal injection, respectively. The Morris water maze (MWZ) was used to evaluate cognitive functions. Moreover, immunofluorescence, RT-qP CR, and Western blot analyses were carried out to evaluate the effects of FP S-ZM1 on neuroinflammation. Network analysis identified 14 crucial targets and highlighted the AGE-RAGE signaling cascade in diabetic complications as the foremost KEGG pathway with potential anti-neuroinflammatory property. MDS results suggested a stable binding of the RAGE-Icariin complex. Remarkably, Icariin was found to effectively mitigate cognitive deficits in VaD mice, which was correlated with the upregulation of the P I3K/AKT pathway and downregulation of the JNK/cJUN signaling cascade. Critically, co-administration of FP S-ZM1 enhanced Icariin’s ameliorative effects on cognitive deficits, owing to bolstered anti-neuroinflammatory action. This study unveils the potential of Icariin in alleviating cognitive dysfunction and neuroinflammation in VaD, which may be attributed to the modulation of the AGE/RAGE pathway. Communicated by Ramaswamy H. Sarma

血管性痴呆（Vascular dementia, VaD）是第二大高发痴呆类型，构成了不容忽视的全球健康挑战。淫羊藿苷（Icariin）已被证实具有强大的神经保护作用，可用于对抗血管性痴呆，然而其发挥作用的具体分子机制尚未完全阐明。本研究采用网络药理学、分子对接及分子动力学模拟（Molecular Dynamics Simulations, MDS）相结合的整合策略，系统探究淫羊藿苷对抗血管性痴呆的潜在药理作用。研究将AGE/RAGE通路（Advanced Glycation End Products/Receptor for Advanced Glycation End Products pathway）鉴定为极具潜力的抗炎通路。本研究采用慢性脑低灌注小鼠模型构建血管性痴呆模型，分别通过灌胃给药与腹腔注射的方式给予淫羊藿苷与FP S-ZM1（一种RAGE抑制剂）。采用莫里斯水迷宫（Morris water maze, MWZ）评估小鼠的认知功能；此外，通过免疫荧光、实时荧光定量聚合酶链反应（Real-time Quantitative Polymerase Chain Reaction, RT-qPCR）与蛋白质印迹分析，评估FP S-ZM1对神经炎症的调控作用。网络分析共筛选出14个关键靶点，并明确糖尿病并发症中的AGE-RAGE信号级联反应是最具潜在抗神经炎症活性的京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路。分子动力学模拟结果显示，RAGE与淫羊藿苷的复合物结合状态稳定。值得注意的是，淫羊藿苷可有效改善血管性痴呆小鼠的认知功能缺损，该作用与磷脂酰肌醇3-激酶/蛋白激酶B（Phosphatidylinositol 3-kinase/AKT, PI3K/AKT）通路的上调以及c-Jun氨基末端激酶/c-Jun（JNK/cJUN）信号级联的下调密切相关。至关重要的是，联合给予FP S-ZM1可增强淫羊藿苷对认知功能缺损的改善作用，这得益于其强化的抗神经炎症活性。本研究揭示了淫羊藿苷可有效缓解血管性痴呆小鼠的认知功能障碍与神经炎症，该作用可能通过调控AGE/RAGE通路实现。本文由Ramaswamy H. Sarma转交刊发。