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

• Published in: Journal of neuroinflammation Vol. 14; no. 1; p. 98
• Main Authors: Ito, Naoki, Hirose, Eiji, Ishida, Tatsuya, Hori, Atsushi, Nagai, Takayuki, Kobayashi, Yoshinori, Kiyohara, Hiroaki, Oikawa, Tetsuro, Hanawa, Toshihiko, Odaguchi, Hiroshi
• Format: Journal Article
• Language: English
• Published: England BioMed Central 03.05.2017; BMC
• Subjects: Animal cognition; Animals; Antidepressant-like effect; Anxiety; Avoidance behavior; Avoidance Learning - drug effects; Avoidance Learning - physiology; Behavior; Brain research; Cell cycle; Chromatography; Chronic fatigue syndrome; Chronic social defeat stress; Citrus fruits; Depression; Drugs, Chinese Herbal - isolation & purification; Drugs, Chinese Herbal - pharmacology; Drugs, Chinese Herbal - therapeutic use; Herbal medicine; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Inflammation; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Kampo; Kososan; Laboratory animals; Lipopolysaccharides; Male; Medicine, Kampo; Mental depression; Mice; Mice, Inbred C57BL; Microglia; Mood; Neurogenesis; Neurosciences; Oral administration; Pathogenesis; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Plant Extracts - therapeutic use; Rodents; Social Behavior; Social interactions; Stress, Psychological - drug therapy; Stress, Psychological - metabolism; Stress, Psychological - pathology; Studies; Japan; Antidepressant-like effect; Kososan; Chronic social defeat stress; Kampo; Depression; Neuroinflammation; Anxiety; Neurogenesis; Microglia
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-017-0876-8

Kososan, 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. In 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. Oral 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. Our 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.