Abstract
BackgroundKososan, a Kampo (traditional Japanese herbal) medicine, has been used for the therapy of depressive mood in humans. However, evidence for the antidepressant efficacy of kososan and potential mechanisms are lacking. Recently, it has been recognized that stress triggers neuroinflammation and suppresses adult neurogenesis, leading to depression and anxiety. Here, we examined whether kososan extract affected social behavior in mice exposed to chronic social defeat stress (CSDS), an animal model of prolonged psychosocial stress, and neuroinflammation induced by CSDS.MethodsIn the CSDS paradigm, C57BL/6J mice were exposed to 10 min of social defeat stress from an aggressive CD-1 mouse for 10 consecutive days (days 1–10). Kososan extract (1.0 g/kg) was administered orally once daily for 12 days (days 1–12). On day 11, the social avoidance test was performed to examine depressive- and anxious-like behaviors. To characterize the impacts of kososan on neuroinflammation and adult neurogenesis, immunochemical analyses and ex vivo microglial stimulation assay with lipopolysaccharide (LPS) were performed on days 13–15.ResultsOral administration of kososan extract alleviated social avoidance, depression- and anxiety-like behaviors, caused by CSDS exposure. CSDS exposure resulted in neuroinflammation, as indicated by the increased accumulation of microglia, the resident immune cells of the brain, and their activation in the hippocampus, which was reversed to normal levels by treatment with kososan extract. Additionally, in ex vivo studies, CSDS exposure potentiated the microglial pro-inflammatory response to a subsequent LPS challenge, an effect that was also blunted by kososan extract treatment. Indeed, the modulatory effect of kososan extract on neuroinflammation appears to be due to a hippocampal increase in an anti-inflammatory phenotype of microglia while sparing an increased pro-inflammatory phenotype of microglia caused by CSDS. Moreover, reduced adult hippocampal neurogenesis in defeated mice was recovered by kososan extract treatment.ConclusionsOur findings suggest that kososan extract prevents a social avoidant behavior in socially defeated mice that is partially mediated by the downregulation of hippocampal neuroinflammation, presumably by the relative increased anti-inflammatory microglia and regulation of adult hippocampal neurogenesis. Our present study also provides novel evidence for the beneficial effects of kososan on depression/anxiety and the possible underlying mechanisms.
Highlights
Kososan, a Kampo medicine, has been used for the therapy of depressive mood in humans
Kososan extract reversed stress-induced social avoidance behaviors in mice The social interaction (SI) ratio was significantly lower in socially defeated mice than in undefeated control mice on the Social avoidance test (SAT) (Fig. 2a; one-way analysis of variance (ANOVA), F(2,53) = 8.064, p < 0.001; post hoc test, p < 0.01)
Our study found that kososan extract treatment prevented the chronic social defeat stress (CSDS)-induced disruption of neurogenesis without reversing the reduction in CX3CR1positive cells and the increase in NLRP3-positive cells caused by stress in the Subgranular zone (SGZ)
Summary
A Kampo (traditional Japanese herbal) medicine, has been used for the therapy of depressive mood in humans. We examined whether kososan extract affected social behavior in mice exposed to chronic social defeat stress (CSDS), an animal model of prolonged psychosocial stress, and neuroinflammation induced by CSDS. Long-lasting exposure to various stressors in humans often causes psychological disorders such as depression. A large body of research has attempted to elucidate the pathogenesis of depression by using animal models exposed to stressors. Chronic social defeat stress (CSDS) is a psychosocial stress behavioral paradigm widely used with face, constructive, and predictive validity [4,5,6] and is currently used to study several psychiatric disorders and their pathologies. CSDS is used to examine depression, anxiety, and the efficacy of therapeutic drugs to treat these conditions [7,8,9]
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