Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0876-8) contains supplementary material, which is available to authorized users.

Dammarane sapogenins attenuates stress‐induced anxiety‐like behaviors by upregulating ERK/CREB/BDNF pathways

“…CSDS is a psychosocial stress behavioral paradigm widely used to study psychiatric disorders, such as anxiety, and their pathologies (Ito et al, 2017). After 6–21 days of CSDS induction, the defeated mice display depressive‐ and anxiety‐like behaviors, including social avoidance, anhedonia and despair (Blanco‐Gandia et al, 2019; Monleon, Duque, & Vinader‐Caerols, 2016).…”

JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress

“…Chronic social defeat stress (CSDS) C57 male mice were subjected to CSDS according to a previously published method with minor modification [48,49]. CD-1 mice are larger and more dominant than C57 mice and are commonly used as aggressors in the social defeat of C57 mice [48,50,51]. Accordingly, we identified aggressive male CD-1 mice as resident aggressors by a 3 day screening process selecting for CD-1 mice that showed at least one aggressive response to an intruder C57 male within 30 s [48].…”

Radix Scutellariae Ameliorates Stress-Induced Depressive-Like Behaviors via Protecting Neurons through the TGFβ3-Smad2/3-Nedd9 Signaling Pathway

“…RS was supplied by Nanjing University of Chinese Medicine and prepared as previously described [ 16 ]. Extracts of RS were prepared by macerating the dried herb in distilled water for 2 h and then boiling two times (100 g/800 ml for 2 h; 100 g/800 ml for 1 h).…”