Mechanism of glutathionein improving depression-like behaviors in post-stroke depressed mice and chronic social defeat stress mice

Yuan ZHAO; Sen LIN; Qingwu YANG

doi:10.16016/j.2097-0927.202401108

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Mechanism of glutathionein improving depression-like behaviors in post-stroke depressed mice and chronic social defeat stress mice

Neuroscience | 更新时间：2026-01-09

- Mechanism of glutathionein improving depression-like behaviors in post-stroke depressed mice and chronic social defeat stress mice
- Journal of Army Medical University Vol. 46, Issue 8, Pages: 775-785(2024)
- 作者机构：
  
  400037 重庆，陆军军医大学(第三军医大学) 第二附属医院神经内科
- 作者简介：
- 基金信息：
  
  the Innovative Group Science Project of Natural Science Foundation of Chongqing(cstc2019jcyj-cxttX0005)
- DOI：10.16016/j.2097-0927.202401108
  CLC： R749.13;R749.4;R977.6
- Received：25 January 2024，
  
  Revised：2024-02-24，
  
  Published：30 April 2024
- 稿件说明：
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Yuan ZHAO, Sen LIN, Qingwu YANG. Mechanism of glutathionein improving depression-like behaviors in post-stroke depressed mice and chronic social defeat stress mice[J]. Journal of Army Medical University, 2024, 46(8): 775-785.
DOI：

Yuan ZHAO, Sen LIN, Qingwu YANG. Mechanism of glutathionein improving depression-like behaviors in post-stroke depressed mice and chronic social defeat stress mice[J]. Journal of Army Medical University, 2024, 46(8): 775-785. DOI： 10.16016/j.2097-0927.202401108.

摘要

目的

探究抑郁症的潜在致病机制及谷胱甘肽的改善作用。

方法

6~8周龄雄性C57BL/6J小鼠分为3组(

=20): 无处理对照(SHAM)组、卒中后抑郁(post-stroke depression，PSD) 模型组和慢性社会挫败应激(chronic social defeat depression，CSDS)模型组。通过旷场实验、高架十字实验、悬尾实验、糖水偏好实验等验证模型小鼠是否有抑郁样行为表现，取2种模型小鼠以及对照小鼠内侧前额叶皮层(medial prefrontal cortex

mPFC)进行神经递质靶向代谢组学测序。通过主成分分析(principle component analysis，PCA)、相关性分析等方法探索各组小鼠代谢物表达情况、筛选差异代谢物，利用京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes，KEGG)预测与抑郁模型相关的代谢通路，并对关键差异代谢物谷胱甘肽(glutathione，GSH)的表达以及丙二醛(malondialdehyde，MDA)、谷胱甘肽过氧化物酶4(glutathione peroxidase 4，GPX4)等铁死亡指标进行检测，外源性补充GSH观察模型小鼠抑郁样行为是否改善。

结果

神经递质靶向代谢组学分析结果显示3组小鼠代谢水平存在明显差异，在mPFC检测到的38种代谢物中，有6种在PSD组中特异性降低，有4种在CSDS组中特异性降低，而GSH、L-天冬酰胺和L-赖氨酸在PSD和CSDS组均表现出明显下降(

＜0.05)。KEGG分析结果显示差异代谢物涉及到的主要通路有谷胱甘肽代谢，β-氨基酸代谢，丙氨酸、天冬氨酸和谷氨酸代谢等通路。还原型谷胱甘肽/氧化型谷胱甘肽(glutathione/oxidized glutathione

GSH/GSSG)试剂盒检测发现两种抑郁模型小鼠mPFC还原型GSH明显减少(

＜0.05)，铁死亡指标检测发现与对照组比较，两种抑郁模型小鼠存在MDA升高并且GPX4阳性细胞比例显著减少的表型(

＜0.05)，而对抑郁模型小鼠外源补充GSH可增加小鼠高架十字实验开臂时间和旷场实验中央区时间(

＜0.05)，并且降低悬尾实验静止不动时间(

＜0.05)，显著改善抑郁样行为表现。

结论

PSD以及CSDS小鼠脑组织存在13种代谢物失调，其中谷胱甘肽代谢异常引发的铁死亡可能在抑郁症发生中具有重要作用，外源性补充谷胱甘肽可以改善小鼠抑郁样行为。

Abstract

Objective

To investigate the potential pathogenesis of depression and the improving effect of glutathione (GSH) in the process.

Methods

Sixty male C57BL/6J mice (6-8 weeks old) were randomly divided into sham operation group (SHAM)

post-stroke depression (PSD) group and chronic social defeat depression (CSDS) group

with 20 animals in each group. Open field test

elevated plus maze test

tail suspension test

and sucrose preference test were performed to identify whether they exhibited depressive-like behaviors. After the tissue samples of medial prefrontal cortex (mPFC) were harvested from the 2 models and control mice

neurotransmitter-targeted metabolomics sequencing was carried out. Principal component analysis (PCA) and correlation analysis were performed to explore the expression of metabolites in each group of mice to screen differential metabolites. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to predict the metabolic pathways related to the depression models. The expression of key differential metabolites related to ferroptosis

including glutathione (GSH)

malondialdehyde (MDA) and glutathione peroxidase 4 (GPX4). The effect of exogenous supplementation of GSH was observed by whether the depressive-like behavior of the model mice was improved.

Results

The results of neurotransmitter-targeted metabolomics analysis showed significant differences in the metabolic levels of the 3 groups of mice. Among the 38 metabolites detected in the mPFC

6 were specifically decreased in PSD and 4 were specifically decreased in CSDS. GSH

L-tryptophan

and L-lysine were significantly decreased in both PSD and CSDS groups (

0.05). KEGG analysis indicated that the main pathways involved in the differential metabolites included GSH metabolism

beta-amino acid metabolism

and alanine

aspartate and glutamate metabolism. GSH/GSSG assay kit indicated that the ratio of reduced GSH/oxidized GSH (GSH/GSSG) in the mPFC of the 2 depression models was significantlly decreased (

0.05)

and the ferroptosis-related index test found that the 2 depression model mice had increased MDA level and significantly reduced GPX4-positive cells compared with the control group (

0.05). Exogenous supplementation of GSH in the depression models extended the open arm time in the elevated plus maze

test

increased the central zone time in the open field test (

0.05)

and reduced the immobility time in the tail suspension test (

0.05)

significantly improving the depressive-like behaviors.

Conclusion

There are 13 metabolite imbalances in the brain tissues of PSD and CSDS mice

and ferroptosis triggered by abnormal GSH metabolism may play an important role in the occurrence of depression. Exogenous supplementation of GSH improves depressive-like behaviors in mice.

关键词

Keywords

references

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