Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Ferulic acid potentiation of two natural iridoids induced PACAP signaling extended the antidepressant effects.
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Ran Shu-Zhen, Peng Rui, Guo Qin-Wan, Zhang Hai-Lou, Zhou Li-Li, Wu Chang-Yu, Xu Zhi-Yang, Wang Zi-Ying, Chen Gang
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.