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肝豆补肾汤通过SIRT3/FOXO3α通路调节褪黑素合成改善Wilson病模型TX小鼠认知障碍

Gandou Bushen Decoction Ameliorates Cognitive Impairment in Wilson Disease Model TX Mice by Regulating Melatonin Synthesis via the SIRT3/FOXO3α Pathway

    摘要
  • 摘要:
    目的  褪黑素已被证明具有神经保护作用，本研究旨在观察铜沉积对Wilson病（Wilson disease, WD）模型TX小鼠认知功能的影响，以及肝豆补肾汤（Gandou Bushen Decoction, GDBSD）对Wilson病模型TX小鼠褪黑素合成及松果体功能的影响及作用机制。
    方法 30只纯合TX小鼠随机分为3组，每组10只：WD组、GDBSD组、二巯丁二酸（dimercaptosuccinic acid, DMSA）组。取10只DL小鼠作为正常对照组(NC组)。使用HE染色、ELISA、流式细胞术和蛋白质印迹等方法检测松果体组织结构和铜含量、氧化应激和细胞凋亡相关标志物、血清褪黑素含量的变化。
    结果  与NC组相比，WD组小鼠学习认知能力下降（P<0.05），松果体组织结构受损，松果体组织中铜含量、活性氧占比和线粒体损伤率升高（P<0.01），褪黑素和氧化应激相关标志物水平改变（P<0.05），促凋亡蛋白Bax、Caspase-3的表达水平上升，抗凋亡蛋白Bcl-2表达减少（P<0.01）。使用肝豆补肾汤及DMSA后，SIRT3/FOXO3α信号通路被激活，松果体组织铜含量下降，氧化应激、细胞凋亡等损伤情况被改善，学习记忆能力好转（P<0.05）。
    结论  肝豆补肾汤可通过抑制松果体氧化应激和细胞凋亡减轻Wilson病铜沉积引起的小鼠认知障碍，其分子机制与调节SIRT3/FOXO3α信号通路有关。

     

    Abstract:
    Objective Melatonin has been shown to have neuroprotective effects. This study is aimed at observing the effects of copper deposition on cognitive function in a toxic milk (TX) mouse model of Wilson disease (WD), and investigating the effects and mechanisms of action of Gandou Bushen Decoction (GDBSD) on melatonin synthesis and pineal function in the WD model mice.
    Methods A total of 30 homozygous TX mice were randomly assigned to 3 groups (n = 10 in each group), including a WD group, a GDBSD group, and a dimercaptosuccinic acid (DMSA) group. A total of 10 DL mice were included in the normal control (NC) group. The structure and copper content of pineal gland tissues, oxidative stress and apoptosis-related markers, and serum melatonin levels were evaluated using hematoxylin-eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and Western blot.
    Results Compared with the NC group, the WD group exhibited decreased learning and cognitive abilities (P < 0.05), damaged pineal gland structure, increased copper content, reactive oxygen species (ROS) levels, and mitochondrial damage rate in the pineal gland (P < 0.01), altered levels of melatonin and oxidative stress-related markers (P < 0.05), upregulated expression levels of pro-apoptotic proteins Bax and Caspase-3, and decreased expression of the anti-apoptotic protein Bcl-2 (P < 0.01). After treatment with GDBSD and DMSA, the SIRT3/FOXO3α signaling pathway was activated, the copper content in the pineal gland was reduced, and oxidative stress and apoptosis-related damages were improved, leading to an improvement in learning and memory abilities (P < 0.05).
    Conclusion GDBSD can alleviate cognitive impairments in WD mice caused by pineal gland copper deposition by inhibiting oxidative stress and apoptosis in the pineal gland. The underlying molecular mechanism is associated with the regulation of the SIRT3/FOXO3α signaling pathway.

     

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