Data_Sheet_1_Integrating serum pharmacochemistry and network pharmacology to reveal the active constituents and mechanism of Corydalis Rhizoma in treating Alzheimer’s disease.docx

BackgroundAlzheimer’s disease (AD) is a multifactorial neurodegenerative condition. The search for multi-target traditional Chinese medicines or ingredients for treating AD has attracted much attention. Corydalis rhizome (CR) is a traditional Chinese medicine. Its main components are alkaloids, which have therapeutic effects that can potentially be used for treating AD. However, no systematic study has been conducted to explore the anti-AD efficacy of CR, as well as its active compounds and mechanisms of action.
ObjectiveThe present study aimed to clarify CR’s active constituents and its pharmacological mechanisms in treating AD.
MethodsA D-galactose & scopolamine hydrobromide-induced AD mouse model was used and CR was administered orally. The prototypical alkaloid components were identified in the serum. The core components, key targets, and possible mechanisms of action of these alkaloids were revealed through network pharmacology. Molecular docking of the key target was performed. Finally, the mechanism was validated by lipopolysaccharide (LPS)-induced activation of BV2 microglia.
ResultsThe results showed that CR improved anxiety-like behavior, spatial and non-spatial recognition, and memory capacity in AD mice. It also achieved synergistic AD treatment by modulating neurotransmitter levels, anti-neuroinflammation, and anti-oxidative stress. The core components that enhance CR’s efficacy in treating AD are protoberberine-type alkaloids. The CR may induce the polarization of LPS-activated BV2 microglia from phenotype M1 to M2. This is partially achieved by modulating the IL-6/JAK2/STAT3 signaling pathway, which could be the mechanism by which CR treats AD through anti-inflammation.
ConclusionThe present study provided a theoretical and experimental basis for the clinical application of CR in treating AD. It also provides information that aids the secondary development, and precise clinical use of CR.

背景：阿尔茨海默病（Alzheimer’s disease, AD）是一种多因素神经退行性疾病。目前，寻找用于治疗AD的多靶点中药或活性成分已受到广泛关注。延胡索（Corydalis rhizome, CR）是一味传统中药，其主要成分为生物碱，该类成分具备潜在的抗AD治疗效应。然而，当前尚无系统性研究探索延胡索的抗AD功效、活性化合物及其作用机制。
目的：本研究旨在阐明延胡索治疗AD的活性成分及其药理学机制。
方法：本研究采用D-半乳糖与氢溴酸东莨菪碱诱导的AD小鼠模型，通过灌胃方式给予延胡索干预；通过血清样本鉴定延胡索的原型生物碱成分；借助网络药理学分析揭示上述生物碱的核心成分、关键靶点及潜在作用机制；对关键靶点开展分子对接验证；最后利用脂多糖（lipopolysaccharide, LPS）诱导的BV2小胶质细胞活化模型对上述机制进行验证。
结果：研究结果表明，延胡索可改善AD小鼠的焦虑样行为、空间与非空间识别能力及记忆功能；其可通过调节神经递质水平、抗神经炎症及抗氧化应激实现协同抗AD治疗。增强延胡索抗AD疗效的核心成分为原小檗碱类生物碱。延胡索可诱导脂多糖活化的BV2小胶质细胞从M1表型向M2表型极化，这一过程部分通过调控IL-6/JAK2/STAT3信号通路实现，该通路或为延胡索通过抗炎途径治疗AD的核心作用机制。
结论：本研究为延胡索治疗AD的临床应用提供了理论与实验依据，同时为其二次开发及精准临床应用提供了参考信息。