Xin Qiqi, Shi Weili, Wang Yan, Yuan Rong, Miao Yu, Chen Keji, Cong Weihong
Laboratory of Cardiovascular Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Front Pharmacol. 2022 Feb 25;13:729605. doi: 10.3389/fphar.2022.729605. eCollection 2022.
To explore the effect and mechanisms of Pantao Pill (PTP) on cognitive impairment. Network pharmacology was performed to analyze the mechanism of PTP treating cognitive impairment. The targets of PTP and cognitive impairment were predicted and used to construct protein-protein interaction (PPI) networks. The intersection network was selected, and the core network was obtained through topological analysis. Enrichment analysis was conducted to obtain the GOBP terms and KEGG pathways. We then performed experiments to validate the results of the network pharmacology by using an APP/PS1 transgenic mouse model. The APP/PS1 mice were divided into four groups: the model group, the high-dose PTP (3.6 g/kg·d) group, the low-dose PTP (1.8 g/kg·d) group, and the positive control group (donepezil hydrochloride, 2 mg/kg·d). Wild-type (WT) C57 mice served as a normal control group. PTP and donepezil were administered by gavage for 8 weeks. Network pharmacology showed that PTP might improve cognitive impairment by regulating autophagy, apoptosis, and oxidative stress. For the Morris water maze test, a significant difference was shown in the total swimming distance among groups ( < 0.05) in the positioning navigation experiment, and with training time extension, the swimming speed increased ( < 0.01). In the space probe test, PTP administration significantly reduced the swimming path length and the escape latency of APP/PS1 mice ( < 0.05 or < 0.01), whereas it had no effect on the swimming speed ( > 0.05). PTP (3.6 g/kg/d) rescued the reduction of norepinephrine and acetylcholine levels ( < 0.05), and increased the acetylcholinesterase concentration ( < 0.05) in the brain tissue. PTP (1.8 g/kg/d) increased the norepinephrine level ( < 0.01). PTP rescued the activity reduction of superoxide dismutase in the brain tissue ( < 0.01) and the neuron cell pyknosis in the hippocampal CA region ( < 0.05). PTP reduced ATG12 and PS1 expression ( < 0.05 or < 0.01), and increased Bcl-2 expression in the brain tissue ( < 0.05). PTP can significantly improve the learning and memory abilities of APP/PS1 mice, and the mechanism may be related to the increase of neurotransmitter acetylcholine and norepinephrine levels, the reduction of the excessive autophagic activation, and the suppression of oxidative stress and excessive apoptotic activity.
探讨蟠桃丸（PTP）对认知障碍的作用及机制。采用网络药理学方法分析PTP治疗认知障碍的机制。预测PTP和认知障碍的靶点并构建蛋白质-蛋白质相互作用（PPI）网络。选取交集网络，通过拓扑分析得到核心网络。进行富集分析以获得基因本体生物学过程（GOBP）术语和京都基因与基因组百科全书（KEGG）通路。然后，我们利用APP/PS1转基因小鼠模型进行实验以验证网络药理学的结果。将APP/PS1小鼠分为四组：模型组、高剂量PTP（3.6 g/kg·d）组、低剂量PTP（1.8 g/kg·d）组和阳性对照组（盐酸多奈哌齐，2 mg/kg·d）。野生型（WT）C57小鼠作为正常对照组。PTP和多奈哌齐通过灌胃给药8周。网络药理学显示，PTP可能通过调节自噬、凋亡和氧化应激来改善认知障碍。在莫里斯水迷宫试验中，定位导航实验中各组间总游泳距离存在显著差异（P<0.05），且随着训练时间延长，游泳速度增加（P<0.01）。在空间探索试验中，给予PTP显著缩短了APP/PS1小鼠的游泳路径长度和逃避潜伏期（P<0.05或P<0.01），而对游泳速度无影响（P>0.05）。PTP（3.6 g/kg/d）可挽救脑组织中去甲肾上腺素和乙酰胆碱水平的降低（P<0.05），并增加乙酰胆碱酯酶浓度（P<0.05）。PTP（1.8 g/kg/d）可增加去甲肾上腺素水平（P<0.01）。PTP可挽救脑组织中超氧化物歧化酶活性降低（P<0.01）和海马CA区神经元细胞固缩（P<0.05）。PTP可降低脑组织中ATG12和PS1的表达（P<0.05或P<0.01），并增加Bcl-2表达（P<0.05）。PTP可显著提高APP/PS1小鼠的学习和记忆能力，其机制可能与神经递质乙酰胆碱和去甲肾上腺素水平升高、过度自噬激活的降低以及氧化应激和过度凋亡活性的抑制有关。
