SIRT1/FOXO1 Axis-Mediated Hippocampal Angiogenesis is Involved in the Antidepressant Effect of Chaihu Shugan San.
SIRT1/FOXO1 Axis-Mediated Hippocampal Angiogenesis is Involved in the Antidepressant Effect of Chaihu Shugan San.
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DOI：
10.2147/dddt.s370825
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发表时间：
2022
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柴胡疏肝散治疗抑郁症历史悠久，临床研究证实其有效、安全。血管生成缺陷在MDD中起重要作用。然而，CSS对血管生成的潜在机制仍然知之甚少。应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。这些目标将在慢性不可预测的轻度应激（CIMIS）诱导的抑郁样小鼠中通过Western印迹，免疫荧光和免疫组织化学进行验证。采用Western blot和免疫荧光技术进一步研究了含CSS血清对脑微血管内皮细胞（BMVECs）的作用机制。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（SIRT 1）/叉头盒O 1（FOXO 1）轴介导的血管生成密切相关。这一预测在以下实验中得到证实。CSS诱导血管生成，增加SIRT 1表达，并减少FOXO 1在海马中的表达。含5% CSS的血清显著增加了BMVECs的增殖、迁移和管形成，但SIRT 1沉默降低了这些作用。CSS血清还可通过SIRT 1信号通路促进FOXO 1向细胞质移位，从而引发FOXO 1蛋白降解。此外，CSS不仅能上调抑郁小鼠海马内VEGFA和BDNF的表达，还能上调BMVECs培养上清中VEGFA和BDNF的表达。值得注意的是，这些营养因子在促进神经发生方面发挥着重要作用。研究表明，CSS可以促进海马神经再生和血管生成。其潜在的分子机制涉及SIRT 1/FOXO 1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SIRT 1/FOXO 1轴可能是治疗MDD的一种有前途的策略。
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.