Abstract
Xiaoyaosan (XYS), as a classic Chinese medicine compound, has been proven to have antidepressant effect in many studies, but its mechanism has not been clarified. In our previous studies, we found that chronic stress can induce depressive-like behavior and lead to emotion-related cingulate gyrus (Cg) dysfunction, as well as the decrease of neurotrophic factors and the increase of inflammatory-related proteins. Therefore, we speculated that XYS may play an antidepressant role by regulating the inflammation-related receptor of advanced glycation protein end product (RAGE) to affect the functional connectivity (FC) signal of the Cg and improve the depressive-like behavior. In order to verify this hypothesis, we analyzed the FC and RAGE expression in the Cg of depressive-like mice induced by chronic unpredictable mild stress (CUMS) and verified it with RAGE knockout mice. At the same time, we detected the effect of XYS on the depressive-like behavior, expression of RAGE, and the FC of the Cg of mice. The results showed that the FC of the Cg of depressive-like mice induced by CUMS was weakened, and the expression of RAGE was upregulated. The antidepressant effect of XYS is similar to that of fluoxetine hydrochloride, which can significantly reduce the depressive-like behavior of mice and inhibit the expression of the RAGE protein and mRNA in the Cg, and increase the FC of the Cg in mice. In conclusion, XYS may play an antidepressant role by downregulating the expression of RAGE in the Cg of depressive-like mice induced by CUMS, thereby affecting the functional signal and improving the depressive-like behavior.
Highlights
Major depressive disorder (MDD), as a complex mental disease, seriously affects people’s physical and mental health, and significantly increases the risk of suicide
Studies have shown that inflammasome produced by the activation of “aseptic inflammation” interacts with damage-associated molecular patterns (DAMPs) to activate the receptor of advanced glycation end products (RAGE) and stimulate inflammatory cascade reaction (Bolos et al, 2018; Franklin et al, 2018; Franklin et al, 2018; Xie et al, 2021)
The results showed that compared with chronic unpredictable mild stress (CUMS) mice, the expression of RAGE in the cingulate gyrus (Cg) of XYS and fluoxetine hydrochloride (FH) mice was significantly decreased (p 0.004, p 0.028, Figures 5G,H), and the expression of RAGE mRNA was decreased (p 0.012, p 0.042, Figure 5I)
Summary
Major depressive disorder (MDD), as a complex mental disease, seriously affects people’s physical and mental health, and significantly increases the risk of suicide. Chronic stress–induced neuroinflammation plays an important role in the progress of MDD (Beurel et al, 2020). It may be a key regulator of disease, increasing the susceptibility to depression (Beurel et al, 2020). Studies have found that in MDD patients, there is a strong relationship between symptoms of depression and inflammatory factors. Chronic inflammation plays a role in the pathophysiology of depression, the mechanism of inflammation activation in emotional disorders and its effect on the brain functional connectivity (FC) are still unclear. In order to clarify its pathogenesis, we can combine it with noninvasive neuroimaging resting-state functional magnetic resonance imaging (rs-fMRI) to further explore the relationship between brain-related inflammatory signals and changes in the brain FC
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