高级检索

    涤痰汤通过JNK/p53信号通路改善阿尔茨海默病大鼠铁死亡及认知功能障碍

    Improvement of Ferroptosis and Cognitive Function Impairment in Alzheimer's Disease Rats by Ditan Decoction via the JNK/p53 Signaling Pathway

      摘要
    • 摘要:
      目的 研究涤痰汤通过调节JNK/p53信号通路来改善阿尔茨海默病(Alzheimer's disease，AD)大鼠的铁死亡和认知功能障碍。
      方法 SPF级雄性SD大鼠60只，随机分为对照组、模型组、多奈哌齐组(阳性对照组，0.00045 g·kg−1)和涤痰汤低、中、高剂量(2.137， 4.275，8.550 g·kg−1)组，每组10只。除对照组外，其余组双侧海马注射β淀粉样蛋白(amyloid β-protein，Aβ)25-35造模。各组每天灌胃给药1次，连续4周。Morris水迷宫试验检测各组逃避潜伏期、跨越平台次数；苏木素-伊红(HE)染色法观察海马区病理形态学变化；透射电镜观察大鼠海马组织中神经元线粒体超微结构变化；流式细胞术检测海马活性氧(reactive oxygen species，ROS)水平；应用生化法检测大鼠海马组织中超氧化物歧化酶(superoxide dismutase，SOD)、谷胱甘肽(glutathione，GSH)和丙二醛(malondialdehyde，MDA)含量；Western blotting及实时荧光定量PCR检测大鼠海马组织c-Jun氨基末端激酶(c-Jun N-terminal kinase，JNK)、p53、溶质载体家族7 成员 11(solute carrier family 7，member 11，SLC7A11)、谷胱甘肽过氧化物酶4(glutathione peroxidase 4，GPX4)、铁蛋白重链1(ferritin heavy chain 1，FTH1)、环氧合酶2(cyclooxygenase-2，COX-2)蛋白及mRNA相对表达水平。
      结果 与模型组比较，涤痰汤干预后可明显提高模型大鼠的学习、空间记忆能力(P<0.05或P<0.01)，减轻海马组织的病理形态学损伤，减轻线粒体损伤，升高SOD、GSH 水平(P<0.05或P<0.01)，降低MDA、ROS水平(P<0.05或P<0.01)，下调JNK、p53、COX-2蛋白及mRNA的表达(P<0.05或P<0.01)，上调SLC7A11、GPX4、FTH1蛋白及mRNA的表达(P<0.05或P<0.01)。
      结论 涤痰汤可改善AD大鼠认知障碍，其机制可能与通过抑制JNK/p53信号通路来抑制铁死亡有关。

       

      Abstract:
      OBJECTIVE  To investigate the effect of Ditan Decoction on ameliorated ferroptosis and cognitive dysfunction in rats with Alzheimer's disease by regulating the JNK/p53 signaling pathway.
      METHODS  Sixty SPF-level male SD rats were randomly divided into control group, model group, donepezil group(positive control group, 0.00045 g·kg−1) and Ditan Decoction low-dose, medium-dose, high-dose(2.137, 4.275, 8.550 g·kg−1) groups with 10 rats in each group. Each group of rats was injected with β-amyloid protein(Aβ)25-35 into the hippocampus to established the model except for the control group. Continued intragastric for 4 weeks and administered once a day. The escape latency and cross-platform times in each group were detected by Morris water maze test. The pathomorphological changes in the hippocampus were observed by Hematoxylin-eosin(HE) staining. The ultrastructural changes of mitochondria in rat hippocampal tissues was used to observed by transmission electron microscopy. The level of reactive oxygen species(ROS) in hippocampal tissue was detected by Flow cytometry. The content of superoxide dismutase(SOD), glutathione(GSH) and malondialdehyde(MDA) in hippocampal tissue of rat were detected by biochemical method. The protein and mRNA relative expression levels of c-Jun amino-terminal kinase(JNK), p53, solute carrier family 7 member 11(SLC7A1), glutathione peroxidase(GPX4), ferritin heavy chain(FTH1) and cyclooxygenase-2(COX-2) in hippocampus was detected by Western blotting and Real-time quantitative polymerase chain reaction(qPCR).
      RESULTS  Compared with the model group, the intervention of Ditan Decoction improved the learning and spatial memory abilities of model rats significantly(P<0.05 or P<0.01), alleviated pathological and morphological damage of hippocampal tissue, reduced mitochondrial damage, increased the level of SOD and GSH and reduced the level of MDA and ROS(P<0.05 or P<0.01), down-regulated the expression of JNK, p53, COX-2 proteins and mRNA(P<0.05 or P<0.01), up-regulated the expression of SLC7A11, GPX4, FTH1 protein and mRNA simultaneously(P<0.05 or P<0.01).
      CONCLUSION  The mechanism of Ditan Decoction improves cognitive impairment in AD rats may be related to inhibited the JNK/p53 signaling pathway and further inhibited the ferroptosis.

       

      • HTML全文
      • 参考文献(29)
      • 相关文章
      • 施引文献
    • 资源附件(0)

    /

    返回文章
    返回