Ito Naoki, Hirose Eiji, Ishida Tatsuya, Hori Atsushi, Nagai Takayuki, Kobayashi Yoshinori, Kiyohara Hiroaki, Oikawa Tetsuro, Hanawa Toshihiko, Odaguchi Hiroshi
Department of Clinical Research, Oriental Medicine Research Center, Kitasato University, Tokyo, Japan.
Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
J Neuroinflammation. 2017 May 3;14(1):98. 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.
小柴胡散是一种日本汉方（传统日本草药）药，已用于治疗人类的抑郁情绪。然而，缺乏小柴胡散抗抑郁疗效及其潜在机制的证据。最近，人们认识到压力会引发神经炎症并抑制成年神经发生，从而导致抑郁和焦虑。在此，我们研究了小柴胡散提取物是否会影响暴露于慢性社会挫败应激（CSDS）的小鼠的社会行为，CSDS是一种长期心理社会应激的动物模型，以及CSDS诱导的神经炎症。
在CSDS范式中，将C57BL/6J小鼠连续10天（第1 - 10天）每天暴露于来自攻击性CD - 1小鼠的10分钟社会挫败应激中。小柴胡散提取物（1.0 g/kg）每天口服给药一次，持续12天（第1 - 12天）。在第11天，进行社会回避试验以检查抑郁样和焦虑样行为。为了表征小柴胡散对神经炎症和成年神经发生的影响，在第13 - 15天进行了免疫化学分析和用脂多糖（LPS）进行的离体小胶质细胞刺激试验。
口服小柴胡散提取物可减轻由CSDS暴露引起的社会回避、抑郁样和焦虑样行为。CSDS暴露导致神经炎症，表现为脑内常驻免疫细胞小胶质细胞的积累增加及其在海马体中的激活，而用小柴胡散提取物治疗可将其逆转至正常水平。此外，在离体研究中，CSDS暴露增强了小胶质细胞对随后LPS刺激的促炎反应，小柴胡散提取物治疗也减弱了这种效应。实际上，小柴胡散提取物对神经炎症的调节作用似乎是由于海马体中抗炎表型的小胶质细胞增加，同时避免了CSDS引起的促炎表型小胶质细胞增加。此外，小柴胡散提取物治疗可恢复受挫小鼠中减少的成年海马神经发生。
我们的研究结果表明，小柴胡散提取物可预防社会挫败小鼠的社会回避行为，这部分是由海马神经炎症的下调介导的，可能是通过相对增加的抗炎小胶质细胞和对成年海马神经发生的调节。我们目前的研究还为小柴胡散对抑郁/焦虑的有益作用及其可能的潜在机制提供了新的证据。
