Improvement effects and mechanism of Zhichi suanzaoren decoction on oxidative stress injury of hippocampal neurons in perimenopausal insomnia mice

LIU Yufei; ZHANG Zeyu; ZHANG Yonghua; HU Linlin; ZHANG Xin

doi:10.6039/j.issn.1001-0408.2025.19.03

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Improvement effects and mechanism of Zhichi suanzaoren decoction on oxidative stress injury of hippocampal neurons in perimenopausal insomnia mice

更新时间：2025-10-11

- Improvement effects and mechanism of Zhichi suanzaoren decoction on oxidative stress injury of hippocampal neurons in perimenopausal insomnia mice
- ZHONGGUO YAOFANG Vol. 36, Issue 19, Pages: 2372-2378(2025)
- 作者机构：
  
  1.浙江中医药大学药学院，杭州　311402
  2.浙江中医药大学附属杭州市中医院睡眠医学中心，杭州　310007
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2025.19.03
  CLC： R965;R285
- Received：11 April 2025，
  
  Revised：2025-08-26，
  
  Accepted：27 August 2025，
  
  Published：15 October 2025
- 稿件说明：
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刘雨霏,张泽宇,张永华,等.栀豉酸枣仁汤对围绝经期失眠小鼠海马神经元氧化应激损伤的改善作用及机制[J].中国药房,2025,36(19):2372-2378.

LIU Yufei,ZHANG Zeyu,ZHANG Yonghua,et al.Improvement effects and mechanism of Zhichi suanzaoren decoction on oxidative stress injury of hippocampal neurons in perimenopausal insomnia mice[J].ZHONGGUO YAOFANG,2025,36(19):2372-2378.
刘雨霏,张泽宇,张永华,等.栀豉酸枣仁汤对围绝经期失眠小鼠海马神经元氧化应激损伤的改善作用及机制[J].中国药房,2025,36(19):2372-2378. DOI： 10.6039/j.issn.1001-0408.2025.19.03.

LIU Yufei,ZHANG Zeyu,ZHANG Yonghua,et al.Improvement effects and mechanism of Zhichi suanzaoren decoction on oxidative stress injury of hippocampal neurons in perimenopausal insomnia mice[J].ZHONGGUO YAOFANG,2025,36(19):2372-2378. DOI： 10.6039/j.issn.1001-0408.2025.19.03.

摘要

目的

探究栀豉酸枣仁汤（ZSD）对围绝经期失眠小鼠海马神经元氧化应激损伤的改善作用及机制。

方法

利用TCMSP和TCMIP数据库预测ZSD中活性成分的潜在靶点，通过GeneCards、OMIM和DisGeNET数据库检索失眠相关靶点，构建两者交集靶点的蛋白质-蛋白质相互作用网络，对关键靶点进行基因本体、京都基因与基因组百科全书通路富集分析。将60只小鼠分为假手术组，模型组，ZSD低、中、高剂量组（11、22、33 g/kg）和右佐匹克隆组（阳性对照，1 mg/kg）。除假手术组外，其余各组均采用双侧卵巢切除术（OVX）构建围绝经期失眠小鼠模型。造模成功后，各组小鼠灌胃生理盐水或相应药液，每天1次，连续3周。通过戊巴比妥钠睡眠协同实验评估小鼠睡眠状况，并利用苏木精-伊红染色、免疫组化染色、免疫荧光染色、转录组测序技术和Western blot法观察小鼠海马神经元病理变化及其相关基因和蛋白表达。

结果

网络药理学结果显示，ZSD与围绝经期失眠共有296个交集靶点，其中蛋白激酶B1（Akt1）是关键靶点之一。ZSD给药后，OVX小鼠睡眠潜伏期显著缩短、睡眠持续期显著延长、海马

CA1区神经元特异性核蛋白平均光密度值显著升高（

＜0.01），且海马神经元损伤明显减轻。转录组测序结果显示，ZSD可显著上调OVX小鼠海马组织中

Nfe2l2

基因的转录水平（

＜0.05）。ZSD给药后，OVX小鼠海马组织中核因子E2相关因子2（Nrf2）、血红素加氧酶1（HO-1）蛋白表达量以及Akt蛋白的磷酸化水平均显著升高（

＜0.01）。

结论

ZSD可通过激活Akt/Nrf2/HO-1信号通路，改善围绝经期失眠小鼠海马神经元氧化应激损伤。

Abstract

OBJECTIVE

To investigate the improvement effects and mechanism of Zhichi suanzaoren decoction （ZSD） on hippocampal oxidative stress injury in hippocampal neurons of mice with perimenopausal insomnia.

METHODS

The potential targets of active ingredients in ZSD were predicted using TCMSP and TCMIP databases； the targets related to insomnia were searched through GeneCards， OMIM and DisGeNET databases； protein-protein interaction network of intersecting targets of ZSD ingredients and insomnia was constructed； Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted on key targets. Sixty mice were divided into sham operation group， model group， ZSD low-， medium-， and high-dose groups （11， 22， and 33 g/kg）， and eszopiclone group （positive control， 1 mg/kg）. Except for sham operation group， the perimenopausal insomnia model was constructed by ovariectomy （OVX） in the other groups. After successful modeling， mice in each group were gavaged with normal saline or the corresponding drug solution， once a day， for three consecutive weeks. The sleep status of mice was evaluated through the pentobarbital sodium sleep synergy experiment， and the pathological changes of hippocampal neurons and the expressions of related genes and proteins in mice were observed by HE staining， immunohistochemistry staining， immunofluorescence staining， transcriptome sequencing technology and Western blot.

RESULTS

The results of network pharmacology showed that there were 296 intersection targets between ZSD and perimenopausal i

nsomnia. Protein kinase B1 （Akt1） was a key target for treating insomnia with ZSD. After administration of ZSD， the sleep latency of mice was shortened， the sleep duration was prolonged significantly， and the mean optical density value of neuron-specific nuclear protein in the hippocampal CA1 region was significantly increased （

＜0.01）. Additionally， hippocampal neuron damage in OVX mice was significantly alleviated. The results of transcriptome sequencing showed that ZSD significantly upregulated the transcriptional levels of

Nfe2l2

gene in hippocampal tissue of OVX mice （

＜0.05）. After administration of ZSD， protein expressions of nuclear factor E2 related factor 2 （Nrf2） and heme oxygenase-1 （HO-1） in hippocampal tissue of OVX mice， as well as the phosphorylated Akt level， were increased significantly （

＜0.01）.

CONCLUSIONS

ZSD can ameliorate hippocampal oxidative stress injury of hippocampal neurons in perimenopausal insomnia mice by activating the Akt/Nrf2/HO-1 signaling pathway.

关键词

Keywords

references

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