Department of Traditional Chinese Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China.
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China.
Drug Des Devel Ther. 2022 Aug 23;16:2783-2801. doi: 10.2147/DDDT.S370825. eCollection 2022.
Chaihu Shugan San (CSS) has a long history for treating major depressive disorder (MDD), which has been verified effectively and safely in clinical studies. Deficient angiogenesis plays important roles in MDD. However, the underlying mechanisms of CSS on angiogenesis remain poorly understood.
Network pharmacology analysis was applied to explore the potential angiogenic targets and pathways between CSS and MDD. These targets would be validated in chronic unpredictable mild stress (CUMS)-induced depressive-like mice by Western blots, immunofluorescence, and immunohistochemistry. Then, the underlying molecular mechanisms were further investigated in brain microvascular endothelial cells (BMVECs) with CSS-containing serum by Western blots and immunofluorescence.
Network pharmacology analysis showed that the antidepressant role of CSS was closely associated with Silent information regulator protein 1 (SIRT1)/Forkhead box O1 (FOXO1) axis-mediated angiogenesis. This prediction was confirmed in the following experiments. CSS induced angiogenesis, increased SIRT1 expression, and decreased FOXO1 expression in the hippocampus of CUMS mice. Five percent CSS-containing serum produced a significant increase in BMVECs proliferation, migration, and tube formation, but these effects were reduced by SIRT1 silencing. CSS serum could also promote FOXO1 translocation to the cytoplasm through SIRT1 signaling, which triggered FOXO1 protein degradation. What is more, CSS upregulated VEGFA and BDNF expressions not only in the hippocampus of depressive mice but also in BMVECs supernatants. Of note, these trophic factors play important roles in promoting neurogenesis.
The study showed that CSS could promote angiogenesis and neurogenesis in the hippocampus of CUMS-induced mice. The underlying molecular mechanism involves the SIRT1/FOXO1 axis and subsequent regulation of VEGFA and BDNF. These findings provide novel insight into CSS drug development, and targeting the SIRT1/FOXO1 axis might be a promising strategy to treat MDD.
柴胡疏肝散（CSS）治疗重度抑郁症（MDD）的历史悠久，在临床研究中已被证明安全有效。血管生成不足在 MDD 中发挥重要作用。然而，CSS 对血管生成的潜在作用机制仍知之甚少。
采用网络药理学分析方法探讨 CSS 与 MDD 之间潜在的血管生成靶点和途径。这些靶点将通过 Western blot、免疫荧光和免疫组化在慢性不可预测轻度应激（CUMS）诱导的抑郁样小鼠中进行验证。然后，通过含有 CSS 的血清在脑微血管内皮细胞（BMVECs）中进一步研究其潜在的分子机制，通过 Western blot 和免疫荧光进行研究。
网络药理学分析表明，CSS 的抗抑郁作用与沉默信息调节蛋白 1（SIRT1）/叉头框 O1（FOXO1）轴介导的血管生成密切相关。这一预测在以下实验中得到了证实。CSS 诱导 CUMS 小鼠海马血管生成，增加 SIRT1 表达，降低 FOXO1 表达。5%CSS 含血清可显著促进 BMVECs 增殖、迁移和管形成，但 SIRT1 沉默可降低这些作用。CSS 血清还可通过 SIRT1 信号转导促进 FOXO1 向细胞质易位，从而触发 FOXO1 蛋白降解。更重要的是，CSS 不仅上调了抑郁小鼠海马中的 VEGFA 和 BDNF 表达，还上调了 BMVECs 上清液中的 VEGFA 和 BDNF 表达。值得注意的是，这些营养因子在促进神经发生中发挥着重要作用。
该研究表明，CSS 可促进 CUMS 诱导的小鼠海马血管生成和神经发生。其潜在的分子机制涉及 SIRT1/FOXO1 轴以及随后对 VEGFA 和 BDNF 的调节。这些发现为 CSS 药物开发提供了新的见解，靶向 SIRT1/FOXO1 轴可能是治疗 MDD 的一种有前途的策略。
