阿魏酸增强两种天然环烯醚萜类化合物诱导的PACAP信号传导延长了抗抑郁作用
Ferulic acid potentiation of two natural iridoids induced PACAP signaling extended the antidepressant effects.
摘要(中文译文)
抑郁症是一种普遍且使人衰弱的疾病，亟需快速起效且持久有效的抗抑郁治疗。近期，我们揭示了来自栀子（Gardenia jasminoides）的两种环烯醚萜类化合物——京尼平苷（geniposide，G）和山栀苷甲酯（shanzhiside methyl ester，S），可通过激活海马PACAP信号通路协同产生快速抗抑郁效应，PACAP信号通路是一种新型抗抑郁靶点。本研究进一步探讨了阿魏酸（ferulic acid，F）的交互作用，阿魏酸是川芎（Ligusticum chuanxiong Hort）的活性成分，川芎常与栀子配伍使用。采用HPLC测定G、S和F的含量。测试了三种化合物在快速和持久抗抑郁效应方面的协同作用。通过光纤记录、Western blotting分子信号检测以及体外或体内药理学或RNAi干预等手段研究了其机制。按比例剂量的G和S混合物（pGS）在30分钟时快速诱导抗抑郁效应并持续24小时，而G、S和F按比例混合物（pGSF）将抗抑郁效应延长至72小时。在机制上，光纤记录显示pGSF诱导了海马神经元激活。pGS和pGSF在30分钟时均增加PACAP表达及下游mTOR蛋白合成信号，但仅pGSF在24小时时激活CREB信号并延长PACAP的上调。体外实验也揭示了三种化合物对CREB信号的协同作用。药理学阻断CREB信号选择性减弱了pGSF的持久抗抑郁效应而不影响其快速作用，而PACAP敲低则完全消除了抗抑郁效应。在LPS诱导的抑郁模型中验证了抗抑郁效应和分子信号。这些发现展示了多化合物对PACAP信号的增强作用，并首次在机制靶向的化合物相互作用层面揭示了时间协同效应。
Abstract
Depression is a prevalent and debilitating disorder, with fast-onset and sustained antidepressant treatment urgently needed. Recently, we revealed two irriods of geniposide (G) and shanzhiside methyl ester (S), both from the herb Gardenia jasminoides, synergistically elicited rapid antidepressant effects by activating hippocampal PACAP signaling, a novel antidepressant target. Here we investigated the further interaction by ferulic acid (F), the active compound from Ligusticum chuanxiong Hort, an herb frequently paired with Gardenia jasminoides. G, S and F were measured by HPLC. The synergism of the three compounds on rapid and sustained antidepressant effects was tested. The mechanisms were examined by using photofiber recording, molecular signaling measurement with western blotting, pharmacological or RNAi interventions in vitro or in vivo. Mixture of proportional dose of G and S (pGS) rapidly induced antidepressant effects at 30 min and sustained for 24 hr, whereas proportional mixture of G, S and F, or pGSF, extended the antidepressant effects to 72 hr. Mechanistically, pGSF induced hippocampal neuronal activation using photofiber recording. Both pGS and pGSF increased PACAP expression and downstream protein synthesis signaling of mTOR at 30 min, but only pGSF activated CREB signaling and prolonged the PACAP upregulation at 24 hr. Synergism of the three compounds on CREB signaling was also revealed in vitro. Pharmacological blockade of CREB signaling selectively attenuated the sustained antidepressant effects of pGSF without affecting its rapid action, whereas antidepressant effects were all abolished by PACAP knockdown. The antidepressant effects and molecular signaling were verified in the LPS-induced depression model. These findings showed multi-compound potentiation of PACAP signaling, and for the first time disclosed the temporal synergism at the mechanism-targeted compound interaction level.
如何引用
AMA
Shu-Zhen Ran, Rui Peng, Qin-Wan Guo, Hai-Lou Zhang, Li-Li Zhou, Chang-Yu Wu, et al. Ferulic acid potentiation of two natural iridoids induced PACAP signaling extended the antidepressant effects.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158185.
APA
Shu-Zhen Ran, Rui Peng, Qin-Wan Guo, Hai-Lou Zhang, Li-Li Zhou, Chang-Yu Wu, et al (2026). Ferulic acid potentiation of two natural iridoids induced PACAP signaling extended the antidepressant effects.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158185
GB/T 7714
Shu-Zhen Ran, Rui Peng, Qin-Wan Guo, Hai-Lou Zhang, Li-Li Zhou, Chang-Yu Wu, et al. Ferulic acid potentiation of two natural iridoids induced PACAP signaling extended the antidepressant effects.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158185.
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