Abstract
Kai-Xin-San (KXS) is a traditional Chinese medicinal formula composed of Ginseng Radix et Rhizoma, Polygalae Radix, Acori Tatarinowii Rhizoma, and Poria for relieving major depressive disorder and Alzheimer’s disease in traditional Chinese medicine (TCM) clinics. Previous studies on the antidepressant mechanism of KXS mainly focused on neurotransmitter and neurotrophic factor regulation, but few reports exist on neuronal inflammation regulation. In the current study, we found that KXS exerted antidepressant effects in chronic unpredictable mild stress-induced depression-like mice according to the results of behavioral tests. Meanwhile, KXS also inhibited the activation of microglia and significantly reduced the expression of pro-inflammatory cytokines such as IL-1β, IL−2, and TNF-α in the hippocampus of mice. In mice BV2 microglia cell lines, KXS extract reduced the expression of inflammatory factors in BV2 cells induced by lipopolysaccharide via inhibiting TLR4/IKK/NF-κB pathways, which was also validated by the treatment of signaling pathway inhibitors such as TAK-242 and JSH-23. T0hese data implied that the regulation of pro-inflammatory cytokines in microglia might account for the antidepressant effect of KXS, thereby providing more scientific information for the development of KXS as an alternative therapy for major depressive disorder.
Highlights
Major depressive disorder (MDD), a widespread mental disorder characterized by the presence of sadness, pleasure loss, and somatic and cognitive changes, has become a serious public health problem (Malhi and Mann, 2018)
Statistical results showed that the consumption of sucrose in the model group was significantly lower than that in the normal control group (p < 0.01), and the immobile time in forced swimming test (FST) and TST was significantly higher than that in the normal group (p < 0.01)
The experimental results showed that the levels of LPS, IL-1β, IL-6, and TNF-α in the hippocampus of CUMS model mice were significantly upregulated compared with those of the normal control group (p < 0.01)
Summary
Major depressive disorder (MDD), a widespread mental disorder characterized by the presence of sadness, pleasure loss, and somatic and cognitive changes, has become a serious public health problem (Malhi and Mann, 2018). An increasing number of studies have shown that chronic inflammation of the central nervous system (CNS) is crucial to the occurrence of depression. The levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the serum of patients with depression are significantly higher than those of normal people (Pape et al, 2019). Animal studies confirmed that persistent chronic stress activates the HPA axis, damages neurons in the hippocampus, and reduces the release of chemokine CX3CL1, which inhibits microglial activation. Microglia are principal immune cells located in the brain responsible for the upregulation of pro-inflammatory mediators upon activation, which is critical for the development of neuronal inflammation in the brain. Chronic overstimulation of microglia can lead to pro-inflammatory mediator release, including pathogenic proteins, cytokines, and chemokines, which significantly and adversely affect neurobiological structure and function. Decreasing the levels of inflammatory cytokines in the brain and reducing neuronal inflammatory damage might be another target for the development of antidepressants (Dantzer, 2018)
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