Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice.
Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice.
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DOI：
10.1186/s12974-017-0876-8
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发表时间：
2017-05-03
影响因子：
9.3
通讯作者：
Odaguchi H
中科院分区：
文献类型：
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作者：
Ito N;Hirose E;Ishida T;Hori A;Nagai T;Kobayashi Y;Kiyohara H;Oikawa T;Hanawa T;Odaguchi H
汉方（传统的日本草药）药物，已被用于治疗人类的抑郁情绪。然而，还缺乏关于可索散抗抑郁疗效和潜在机制的证据。最近，人们已经认识到，压力触发神经炎症和抑制成人神经发生，导致抑郁和焦虑。在这里，我们研究了Kosossan提取物是否影响慢性社会失败应激（CSDS）小鼠的社会行为，长期的心理社会应激的动物模型，以及CSDS诱导的神经炎症。在CSDS范例中，将C57 BL/6 J小鼠暴露于来自攻击性CD-1小鼠的10分钟社交失败应激，持续10天（第1-10天）。连续12天（第1-12天）每天一次经口给予党参提取物（1.0 g/kg）。在第11天，进行社交回避测试以检查抑郁和焦虑样行为。为了表征kososan对神经炎症和成体神经发生的影响，在第13-15天进行免疫化学分析和用脂多糖（LPS）的离体小胶质细胞刺激测定。口服给药的kosossan提取物减轻社会回避，抑郁和焦虑样行为，引起的CSDS曝光。CSDS暴露导致神经炎症，如通过小胶质细胞（大脑的常驻免疫细胞）的积累增加以及它们在海马中的活化所指示的，其通过用Kososan提取物处理逆转至正常水平。此外，在离体研究中，CSDS暴露增强了小胶质细胞对随后的LPS攻击的促炎反应，这种作用也被kososan提取物处理减弱。事实上，Kosososan提取物对神经炎症的调节作用似乎是由于小胶质细胞的抗炎表型的海马增加，同时保留了由CSDS引起的小胶质细胞的促炎表型的增加。此外，减少成年海马神经再生失败的小鼠恢复了kosossan提取物治疗。我们的研究结果表明，Kosososan提取物防止社交失败的小鼠的社交回避行为，这部分是通过下调海马神经炎症介导的，可能是通过相对增加的抗炎小胶质细胞和成年海马神经发生的调节。本研究也为Kosososan对抑郁/焦虑的有益作用及其可能的机制提供了新的证据。本文的在线版本（doi：10.1186/s12974-017-0876-8）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s12974-017-0876-8) contains supplementary material, which is available to authorized users.