Hippocampal pituitary adenylate cyclase–activating polypeptide mediates rapid antidepressant-like effects of Yueju pill

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides Pub Date : 2023-10-01 DOI:10.1016/j.npep.2023.102350

Li Ren , Hailou Zhang , Weiwei Tao , Wenda Xue , Yin Chen , Zhilu Zou , Xiaoyan Guo , Qinqin Shen , Wei Wang , Haitang Jiang , Juanjuan Tang , Quansheng Feng , Gang Chen

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Abstract

Yueju pill, a classic Chinese Medicine formulated, was recently found to produce rapid antidepressant-like effects in a PKA-CREB signaling-dependent manner. In our study, we found that the Yueju pill induced a remarkable increase in PACAP. The intracerebroventricular injection of PACAP agonist induced a rapid antidepressant-like effect; conversely, the intrahippocampal infusion of a PACAP antagonist reversed the antidepressant response of the Yueju pill. Mice with hippocampal PACAP knockdown via viral-mediated RNAi displayed depression-like behavior. PACAP knockdown also blunted the antidepressant effect of the Yueju pill. PACAP knockdown resulted in down-regulated CREB and expression of the synaptic protein PSD95 at both baselines and after administration of the Yueju pill. However, administration of the Yueju pill in the knockdown mice promoted PACAP and PKA levels. Chronically stressed mice showed deficient hippocampal PACAP-PKA-CREB signaling and depression-like behavior, which were reversed by a single dose of the Yueju pill. In this study, we demonstrated that the up-regulation of PACAP induced activating of PKA-CREB signaling would play a part in the rapid antidepressant-like effects of the Yueju pill. We also identified iridoids fraction of Gardenia jasminoides Ellis (GJ-IF), a vital component of the Yueju pill, was identified to recapitulate rapid antidepressant-like behavior through increased hippocampal PACAP expression of the Yueju pill. The promotion of hippocampal PACAP may collectively represent a novel mechanism of rapid antidepressant-like effect.

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海马垂体腺苷酸环化酶激活多肽介导粤菊丸快速抗抑郁样作用

越橘丸是一种经典的中药配方，最近被发现以PKA-CREB信号依赖的方式产生快速的抗抑郁作用。在我们的研究中，我们发现越橘丸诱导PACAP显著增加。侧脑室注射PACAP激动剂可诱导快速的抗抑郁作用；相反，海马内输注PACAP拮抗剂逆转了越橘丸的抗抑郁反应。通过病毒介导的RNAi敲低海马PACAP的小鼠表现出抑郁样行为。PACAP的降低也削弱了越橘丸的抗抑郁作用。PACAP敲低导致CREB和突触蛋白PSD95在基线和服用越橘丸后的表达下调。然而，在敲除小鼠中施用越橘丸促进了PACAP和PKA水平。慢性应激小鼠表现出海马PACAP-PKA-CREB信号传导不足和抑郁样行为，单剂量越橘丸可逆转这种情况。在本研究中，我们证明了PACAP诱导的PKA-CREB信号激活的上调将在越橘丸的快速抗抑郁作用中发挥作用。我们还鉴定了越橘丸的重要成分栀子（GJ-IF）的环烯醚萜类成分，该成分通过增加越橘丸海马PACAP的表达来重现快速抗抑郁样行为。海马PACAP的促进可能共同代表了一种快速抗抑郁作用的新机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropeptides 医学-内分泌学与代谢

CiteScore

5.40

自引率

6.90%

发文量

审稿时长

>12 weeks

期刊介绍： The aim of Neuropeptides is the rapid publication of original research and review articles, dealing with the structure, distribution, actions and functions of peptides in the central and peripheral nervous systems. The explosion of research activity in this field has led to the identification of numerous naturally occurring endogenous peptides which act as neurotransmitters, neuromodulators, or trophic factors, to mediate nervous system functions. Increasing numbers of non-peptide ligands of neuropeptide receptors have been developed, which act as agonists or antagonists in peptidergic systems. The journal provides a unique opportunity of integrating the many disciplines involved in all neuropeptide research. The journal publishes articles on all aspects of the neuropeptide field, with particular emphasis on gene regulation of peptide expression, peptide receptor subtypes, transgenic and knockout mice with mutations in genes for neuropeptides and peptide receptors, neuroanatomy, physiology, behaviour, neurotrophic factors, preclinical drug evaluation, clinical studies, and clinical trials.