摘要
目的预测并验证开心散(简称“KXS”)改善阿尔茨海默病(AD)神经炎症的潜在机制。方法采用网络药理学方法,挖掘KXS用于AD的核心抗炎成分及核心炎症靶点,进行基因本体(GO)功能、京都基因和基因组数据库(KEGG)通路富集分析,并进行分子对接。基于网络药理学结果,以雄性SD大鼠为对象,以D-半乳糖慢性诱导建立AD模型,考察KXS对AD大鼠体征量化评分、学习记忆能力指标(逃避潜伏期、穿越平台次数、平台象限路程及时间)、脏器(心脏、肝脏、脾脏、胸腺)指数、海马组织病理改变以及炎症相关通路及上下游蛋白表达的影响。结果KXS用于AD的核心抗炎成分包括五味子酯乙、人参炔三醇、五味子酯甲、enhydrin、vulgarin、人参环氧炔醇,核心炎症靶点包括核因子κB亚基1、核因子κB p65(NF-κB p65)、白细胞介素1β(IL-1β)、IL-6、Toll受体4(TLR4)、肿瘤坏死因子、核苷酸结合结构域富含亮氨酸重复序列和含热蛋白结构域受体3(NLRP3)、胱天蛋白酶1(CASP1);GO、KEGG富集结果涉及炎症反应、磷酸化途径及NF-κB炎症通路;核心抗炎成分与核心炎症靶点之间具有较强的结合能力。动物实验显示,与模型组比较,KXS组大鼠海马组织CA1、CA3、DG区神经元皱缩、尼氏体减少等病理改变均有改善,脏器指数(肝脏指数除外)、尼氏染色阳性细胞数均显著升高或增多,学习记忆能力指标均显著改善,体征量化评分(实验第8、12周)和NF-κB p65、磷酸化NF-κB p65、TLR4、NLRP3、CASP1、IL-1β蛋白的表达均显著降低或下调。结论KXS能有效改善AD大鼠神经炎症,减轻海马神经元损伤,提高学习记忆能力;上述作用可能与抑制NF-κB信号通路及其上下游相关蛋白的表达有关。
OBJECTIVE To predict and validate the potential mechanisms of Kaixinsan(KXS)in ameliorating neuroinflammation in Alzheimer’s disease(AD).METHODS Network pharmacology was employed to identify core antiinflammatory components and key inflammatory targets of KXS for AD.Gene ontology(GO)functional annotation,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment,and molecular docking were performed.Based on these findings,male SD rats were used to establish an AD model via chronic D-galactose induction.The effects of KXS on AD rats were evaluated,including quantitative behavioral score,learning and memory parameters(escape latency,platform crossings,platform quadrant distance and time),organ indexes(heart,liver,spleen,thymus),histopathological alterations in the hippocampus,and expressions of inflammation-related pathway proteins and their upstream/downstream regulators.RESULTS Core anti-inflammatory components of KXS for AD included gomisin B,panaxytriol,gomisin A,enhydrin,vulgarin and panaxydol,while key inflammatory targets involved nuclear factor-kappa B subunit 1(NFKB1),nuclear factor-κB p65(NF-κB p65),interleukin-1β(IL-1β),IL-6,Toll-like receptor 4(TLR4),tumor necrosis factor,nucleotide-binding domain leucine-rich repeat and pyrin domaincontaining receptor 3(NLRP3)and caspase-1(CASP1).GO and KEGG pathway enrichment involved inflammatory response,phosphorylation and the NF-κB signaling pathway.Molecular docking confirmed strong binding affinities between core components and key targets.Animal experiments demonstrated that,compared to the model group,KXS significantly alleviated histopathological damage(e.g.,neuronal shrinkage,reduced Nissl bodies in hippocampal CA1,CA3,and DG regions),increased organ indexes(except for liver index)and Nisslstained positive cells,improved learning and memory performance,and reduced behavioral scores(at the 8 and 12 weeks of the experiment)and protein expression of NF-κB p65,phosphorylated NF-κB p65,TLR4,NLRP3,CASP1 and IL-1β.CONCLUSIONS KXS effectively mitigates neuroinflammation,reduces hippocampal neuronal injury,and enhances learning and memory ability in AD rats,potentially through suppressing the NF-κB signaling pathway and its upstream/downstream regulators.
作者
徐丹丹
曾永长
梁少瑜
刘琦
吴俊洪
何康
XU Dandan;ZENG Yongchang;LIANG Shaoyu;LIU Qi;WU Junhong;HE Kang(School of Pharmacy,Guizhou University of Traditional Chinese Medicine,Guiyang 550025,China;Preparation Department,the Affiliated Hospital of Traditional Chinese Medicine,Guangzhou Medical University,Guangzhou 510140,China;Geriatric Medicine Institute,Shenzhen Second People’s Hospital,Guangdong Shenzhen 518035,China)
出处
《中国药房》
北大核心
2025年第12期1476-1482,共7页
China Pharmacy
基金
广东省自然科学基金项目(No.2021A1515010978,No.2021A1515012474)
深圳市科技创新委员会基础研究项目(No.JCYJ20210324121610029)。
