Synergistic effects of two naturally occurring iridoids in eliciting a rapid antidepressant action by up-regulating hippocampal PACAP signalling

Hailou Zhang, Yan Sun, Suk Yu Yau, Yanmeng Zhou, Xinxin Song, Han Ting Zhang, Boran Zhu, Haoxin Wu, Gang Chen (Corresponding Author)

Research output: Journal article publicationJournal articleAcademic researchpeer-review

Abstract

Background and purpose: Current mainstream antidepressants have limited efficacy with a delayed onset of action. Yueju, a herbal medicine, has a rapid antidepressant action. Identification of the active ingredients in Yueju and the mechanism/s involved was carried out.

Experimental approach: Key molecule/s and compounds involved in this antidepressant action was identified by transcriptomic and HPLC analysis, respectively. Antidepressant effects were evaluated using various behavioural experiments. The signalling involved was assessed using site-directed pharmacological intervention or optogenetic manipulation.

Key results: Transcriptomic analysis showed that Yueju up-regulated pituitary adenylate cyclase activating polypeptide (PACAP) expression in the hippocampus. Two iridoids, geniposide and shanzhiside methyl ester, were identified and quantified from Yueju. Only co-treatment with both, at an equivalent concentrations found in Yueju, increased PACAP expression and elicited a rapid antidepressant action, which were blocked by intra-dentate gyrus infusion of a PACAP antagonist or optogenetic inactivation of PACAP expressing neurons. Geniposide and shanzhiside methyl ester co-treatment rapidly inhibited CaMKII phosphorylation and enhanced mTOR/4EBP1/P70S6k/BDNF ignalling, while intra-dentate gyrus infusions of a CaMKII activator blunted the rapid antidepressant action and BDNF expression up-regulation induced by the co-treatment. A single co-treatment of them rapidly improved depression-like behaviours and up-regulated hippocampal PACAP signalling in the repeated corticosterone-induced depression model, further confirming the involvement of PACAP.

Conclusion and implications: Geniposide and shanzhiside methyl ester co-treatment had a synergistic rapid onset antidepressant action by triggering hippocampal PACAP activity and associated CaMKII-BDNF signalling. This mechanism could be targeted for development of fast onset antidepressants.
Original languageEnglish
Pages (from-to)4078-4091
Number of pages14
JournalBritish Journal of Pharmacology
Volume179
Issue number16
Early online date31 Mar 2022
DOIs
Publication statusPublished - Aug 2022

Keywords

  • BDNF
  • CaMKII
  • PACAP
  • novelty-suppressed feeding test
  • rapid antidepressant
  • synergism

ASJC Scopus subject areas

  • Pharmacology

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