Li Meihong, Nie Bin, Liu Jieqiong, Li Zhen, Luo Fang, Ye Yingze
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Int Immunopharmacol. 2025 Oct 10;163:115213. doi: 10.1016/j.intimp.2025.115213. Epub 2025 Jul 18.
Ischemic stroke remains a major contributor to disability and mortality, emphasizing the urgent need for new therapies to enhance reperfusion treatment outcomes. In this study, we systematically investigated the neuroprotective effects of matrine, an alkaloid derived from Sophora flavescens, using both computational and experimental approaches. Initially, a network pharmacology strategy was employed to identify 69 potential targets of matrine relevant to ischemic stroke by integrating data from Swiss Target Prediction, Similarity Ensemble Approach, PharmMapper, and GeneCards. Subsequent protein-protein interaction analyses, along with GO and KEGG pathway enrichment, highlighted the AMPK signaling pathway as a critical mediator. To validate these findings, male C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAO) to induce stroke. Matrine treatment in this model resulted in significant improvements in neurological function, reductions in brain damage, and marked decreases in oxidative stress and apoptosis. Furthermore, molecular docking and molecular dynamics (MD) simulations studies revealed a strong binding affinity between matrine and key targets such as AMPK, CHRNA4, and SLC6A3, with Western blot analyses confirming the involvement of AMPK and its upstream regulator UCP2. Collectively, our results demonstrate that matrine confers neuroprotection in cerebral ischemia-reperfusion injury by modulating the AMPK pathway, suggesting its potential as a novel therapeutic agent for ischemic stroke. The proposed mechanisms of matrine in ischemic stroke are summarized in the graphical abstract.
缺血性中风仍然是导致残疾和死亡的主要原因，这凸显了迫切需要新的疗法来提高再灌注治疗效果。在本研究中，我们使用计算和实验方法系统地研究了苦参碱（一种从苦参中提取的生物碱）的神经保护作用。最初，采用网络药理学策略，通过整合来自瑞士靶点预测、相似性集成方法、PharmMapper和基因卡的数据，确定了69个与缺血性中风相关的苦参碱潜在靶点。随后的蛋白质-蛋白质相互作用分析以及GO和KEGG通路富集分析表明，AMPK信号通路是关键介质。为了验证这些发现，对雄性C57BL/6J小鼠进行大脑中动脉闭塞（MCAO）以诱导中风。在该模型中，苦参碱治疗导致神经功能显著改善、脑损伤减轻以及氧化应激和细胞凋亡明显减少。此外，分子对接和分子动力学（MD）模拟研究表明，苦参碱与AMPK、CHRNA4和SLC6A3等关键靶点之间具有很强的结合亲和力，蛋白质印迹分析证实了AMPK及其上游调节因子UCP2的参与。总的来说，我们的结果表明，苦参碱通过调节AMPK通路在脑缺血再灌注损伤中发挥神经保护作用，表明其作为缺血性中风新型治疗药物的潜力。苦参碱在缺血性中风中的作用机制在图形摘要中进行了总结。
