Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus

Abstract

Background At present, the pathogenesis of depression is not fully understood, and nearly half of depression patients experience no obvious effects during treatment. This study aimed to establish a depression mouse model to explore the possible role of ferroptosis in the pathogenesis of depression, and observe the effects of Xiaoyaosan on PEBP1-GPX4-mediated ferroptosis in the hippocampus. Methods Forty-eight male C57BL/6 mice were randomly divided into a control group, CUMS group, Xiaoyaosan group and fluoxetine group, and the model was established by chronic unpredictable mild stress (CUMS) for a successive 6 weeks. The medication procedure was performed from the 4th to the 6th week of modeling. The behavioral evaluations were measured to evaluate depressive-like behaviors. The expressions of GPX4, FTH1, ACSL4 and COX2 were detected as ferroptosis-related indicators. Then, the total iron and ferrous content in the hippocampus were measured. The levels of PEBP1 and ERK1/2 were observed, and the expressions of GFAP and IBA1 were also detected to measure the functions of astrocytes and microglia in the hippocampus. Results Eight herbs of Xiaoyaosan had 133 active ingredients which could regulate the 43 ferroptosis-related genes in depression. After 6 weeks of modeling, the data showed that mice in the CUMS group had obvious depressive-like behaviors, and medication with Xiaoyaosan or fluoxetine could significantly improve the behavioral changes. The expressions of GPX4, FTH1, ACSL4, COX2, PEBP1, ERK1/2, GFAP and IBA1 changed in the CUMS group mice, while the total iron and ferrous content also changed. Xiaoyaosan and fluoxetine had obvious curative effects that could significantly alleviate the above changes in the hippocampus. Conclusion Our results revealed that the activation of ferroptosis might exist in the hippocampi of CUMS-induced mice. The PEBP1-GPX4-mediated ferroptosis could be involved in the antidepressant mechanism of Xiaoyaosan. It also implied that ferroptosis could become a new target for research into the depression mechanism and antidepressant drugs.

Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder

“…Genes involved in ferroptosis were differentially regulated; specifically, glutathione peroxidase (GPX4, necessary for repairing oxidative damage) was downregulated after CUMS suggesting a role of ferroptosis in the phenotype of depression. In addition, this study also showed that fluoxetine not only resolved depressive behaviors but also restored normal ferroptosis signaling ( 360 ). Experimental models also display an increase in iron load in the brain which results in anxiety symptoms.…”

Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders

“…The research on the mechanism and the treatment of anxiety and depression have also attracted extensive attention. Jiao et al [95] found that the contents of total iron and ferrous ion in the hippocampus of chronic unpredictable mild stress (CUMS) model mice increased, and GPX4, FTH1, ACSl4, and COX-2 also changed significantly, which proved the evidence of ferroptosis in the hippocampus of the depression mouse model. Previous research reported that sodium hydrosulfide (NaHS) can alleviate the depressive and anxiety-like behaviors induced by type 1 diabetes mellitus (T1DM) [96].…”

Sesamol ameliorates dextran sulfate sodium-induced depression-like and anxiety-like behaviors in colitis mice: the potential involvement of the gut–brain axis

“…8,10,15,45 In other animal research studies, such as those focusing on olfactory bulbectomized (OBX)-induced depression and chronic unpredictable mild stress (CUMS)-induced depression, there was a marked increase in the expressions of Iba1 and GFAP, which indicate the activation of microglia and astrocytes, respectively. 46,47 Interestingly, available evidence from previous studies also shows that activated microglia and astrocytes are found to be intimately involved in depression. 48 Also consistent with the previous findings, we observed that astrocytes and microglia were activated and the mRNA expressions of TLR-4, iNOS, Cox-2, TNF-α, IL-6 and IL-1β in the cortex were notably enhanced, while in the mice administered sesamol, microglia and astrocyte activation was inhibited as well as there was an increase of inflammatory cytokines (Fig.…”