Cheng Zizhao, Wang Shengyao, Hua Xuesi, Zhang Li, Li Boya, Li Huiling, Bai Yunya, Li Yali, Hao Jinping, Wang Jianxiong, Zhao Lingyi, Gao Dan, Zhang Lan
Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Beijing 100053, China.
Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
J Pharm Biomed Anal. 2025 Aug 1;260:116818. doi: 10.1016/j.jpba.2025.116818. Epub 2025 Mar 12.
Given the growing incidence of dementia-related disorders in the aging population, identifying effective treatments for age-related cognitive decline (ARCD) is crucial. Shenwu Capsule (SWC), shown to have therapeutic efficacy in phase III clinical trials for senile dementia, has unclear mechanisms and active ingredients. Aged mice were administered SWC orally for three months, and behavioral tests, including the Morris water maze, Y maze, and novel object recognition, assessed learning and memory. Neuronal damage was evaluated using histopathology, and the levels of Aβ and phosphorylated tau proteins were measured. UPLC-Q-TOF-MS identified 11 components of SWC capable of crossing the blood-brain barrier (BBB), and network pharmacology was employed to explore their potential mechanisms. Through various detection methods, including transmission electron microscopy, Western blotting, qRT-PCR, ELISA, and immunofluorescence, six key targets (AKT1, TNF, TP53, SRC, EGFR, BCL2) were elucidated. GO and KEGG pathway analyses revealed that the PI3K/Akt signaling pathway plays a crucial role in the pharmacological effects of SWC. SWC was found to suppress neuronal apoptosis by activating the PI3K/Akt/Bcl-2 signaling pathway, as demonstrated by changes in mRNA and protein levels. Histological analysis further showed that SWC treatment restored mitochondrial morphology in the hippocampus of aged mice. Molecular docking simulations confirmed strong binding affinities between the active components and key targets. Psoralidin, a component with strong molecular docking potential, was shown in vitro to activate the PI3K/Akt/Bcl-2 pathway, reduce ROS, decrease apoptosis, improve mitochondrial morphology, and stabilize mitochondrial membrane potential. These protective effects were blocked by the PI3K inhibitor LY294002. Overall, SWC ameliorates ARCD through modulation of the PI3K/Akt/Bcl-2 signaling pathway, with psoralidin identified as a potential active ingredient.
鉴于老年人口中与痴呆相关疾病的发病率不断上升，确定针对年龄相关性认知衰退（ARCD）的有效治疗方法至关重要。参乌胶囊（SWC）在老年性痴呆的III期临床试验中显示出治疗效果，但其作用机制和活性成分尚不清楚。对老年小鼠口服SWC三个月，并通过包括莫里斯水迷宫、Y迷宫和新物体识别在内的行为测试评估学习和记忆。使用组织病理学评估神经元损伤，并测量Aβ和磷酸化tau蛋白的水平。超高效液相色谱-四极杆飞行时间质谱法（UPLC-Q-TOF-MS）鉴定出11种能够穿过血脑屏障（BBB）的SWC成分，并采用网络药理学探索其潜在机制。通过包括透射电子显微镜、蛋白质免疫印迹法、实时定量聚合酶链反应、酶联免疫吸附测定和免疫荧光在内的各种检测方法，阐明了六个关键靶点（AKT1、TNF、TP53、SRC、EGFR、BCL2）。基因本体（GO）和京都基因与基因组百科全书（KEGG）通路分析表明，PI3K/Akt信号通路在SWC的药理作用中起关键作用。如mRNA和蛋白质水平的变化所示，发现SWC通过激活PI3K/Akt/Bcl-2信号通路抑制神经元凋亡。组织学分析进一步表明，SWC治疗可恢复老年小鼠海马体中的线粒体形态。分子对接模拟证实了活性成分与关键靶点之间有很强的结合亲和力。补骨脂素是一种具有很强分子对接潜力的成分，体外实验表明它能激活PI3K/Akt/Bcl-2通路、减少活性氧（ROS）、降低细胞凋亡、改善线粒体形态并稳定线粒体膜电位。这些保护作用被PI3K抑制剂LY294002阻断。总体而言，SWC通过调节PI3K/Akt/Bcl-2信号通路改善ARCD，补骨脂素被确定为一种潜在的活性成分。
