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

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 (P < 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 (P < 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 (P < 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 (P < 0.05), and reduced the immobility time in the tail suspension test (P < 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.

Keywords

• post-stroke depression
• chronic social defeat stress
• metabolome
• glutathione
• ferroptosis