香附中PDE4酶抑制剂的发现及其激活cAMP/PKA/CREB/BDNF通路发挥抗抑郁的分子机制

The iridoid glycosides from Cyperus rotundus acts well on antidepression and its antitdepressant effect is superior to the positive control drug fluoxetine has been proved by integrated multi-model screening. Furthermore, its antidepressant activity is closely related to a signaling transduction pathway: cAMP/PKA/CREB/BDNF and a enzyme: PDE4. On the basis, 29 iridoid compounds were isolated from the rhizomes of Cyperus rotundus. However, whether the above iridoid compounds have antidepressant activity? Are their antidepressant mechanism of action closely associated with the above signaling transduction pathway and PDE4? In order to elucidate the antidepressant active components from Cyperus rotundus and their mechanism, the isolation and identification of antidepressant iridoid ingredients form the Cyperus rotundus will be studied. Then, methods of rats model of chronically depressive stress, immunohistochemistry and western blot will be adopted to analyze influences of the antidepressant active components from Cyperus rotundus on “cAMP/PKA/CREB/BDNF” signaling transduction pathway. The research results of this project will establish a solid foundation for discovering antidepressant active components and leading compounds, and demonstrate theoretical as well as practical values.

前期多模型筛选证实香附总环烯醚萜苷具有明确的抗抑郁活性，其作用优于氟西汀并且与磷酸二酯酶4（PDE4）以及cAMP/PKA/CREB/BDNF信号转导通路有密切关联。在此基础上，从香附中系统分离鉴定了29个环烯醚萜苷。但香附环烯醚萜苷单体是否具有抗抑郁活性？其作用机制是否通过抑制PDE4酶，进而激活cAMP/PKA/CREB/BDNF通路发挥抗抑郁作用？本项目以香附环烯醚萜苷类成分为重点，以PDE4酶为靶标，将进一步系统筛选香附抗抑郁活性成分；采用大鼠慢性应激抑郁模型、免疫组织化学、蛋白印迹等研究方法，详细分析它们对cAMP/PKA/CREB/BDNF信号转导通路的调节作用，从分子水平阐明香附环烯醚萜苷类成分激活该通路发挥抗抑郁作用的分子生物学机制。本研究为寻找具有抗抑郁的中草药活性成分、发现治疗抑郁症药物先导化合物奠定基础，具有重要的理论研究意义和应用价值。

抑郁症是一种高患病率、高致残率以及高自杀率的严重精神性疾患，属于情感性精神障碍。中药及天然药物是抗抑郁先导化合物和新药发现的重要来源。我们前期工作表明香附总环烯醚萜苷具有明确的抗抑郁活性，其作用优于阳性药氟西汀且与磷酸二酯酶4（PDE4）以及cAMP/PKA/CREB/BDNF信号通路有密切关联。本项目研究了中药香附（Cyperus rotundus L.）中PDE4酶抑制剂发现、抗抑郁活性成分筛选及其富集制备和作用机制研究。从中药香附抗抑郁有效部位筛选得到19个PDE4酶抑制剂，包括12个环烯醚萜苷、4个三萜皂苷和3个酚类化合物。其中，7个PDE4酶抑制剂具有较强的抗抑郁活性，并建立了这7个抗抑郁活性成分富集制备方法。作用机制研究表明，7个香附抗抑郁活性成分通过抑制PDE4酶，进而激活cAMP/PKA/CREB/BDNF通路发挥抗抑郁作用，并发表SCI收录论文5篇，会议论文1篇。本项目属于基础研究，为新药开发提供理论和实验依据，具有重要的理论研究意义和应用价值。