The Rapid and Long-Lasting Antidepressant Effects of Iridoid Fraction in Gardenia Jasminoides J.Ellis Are Dependent on Activating PKA-CREB Signaling Pathway

Li Ren; Hailou Zhang; Weiwei Tao; Yin Chen; Zhilu Zou; XiaoYan Guo; Qinqin Shen; Quansheng Feng; Jingqing Hu

doi:10.3389/fphar.2022.896628

The Rapid and Long-Lasting Antidepressant Effects of Iridoid Fraction in Gardenia Jasminoides J.Ellis Are Dependent on Activating PKA-CREB Signaling Pathway

Front Pharmacol. 2022 Jun 8:13:896628. doi: 10.3389/fphar.2022.896628. eCollection 2022.

Authors

Li Ren¹, Hailou Zhang², Weiwei Tao³, Yin Chen³, Zhilu Zou³, XiaoYan Guo³, Qinqin Shen³, Quansheng Feng¹, Jingqing Hu⁴

Affiliations

¹ School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
² Interdisciplinary Institute for Personalized Medicine in Brain Disorders and School of Chinese Medicine, Jinan University, Guangzhou, China.
³ Basic Teaching and Research Department of Integrated Chinese and Western Medicine, College of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
⁴ Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China.

Abstract

Lag periods of therapeutic efficacy cause poor compliance of patients, which has made solutions for rapid antidepressants the most urgent need in the depression study field at present. We have identified through our previous studies the rapid antidepressant effects of the traditional herb Gardenia jasminoides J.Ellis [Rubiaceae] (GJ) and its standardized fractions. Through screening different fractions of GJ, we decided to place our focus on the iridoid fraction of GJ (GJ-IF). Methods: 1. Tail suspension test (TST), forced swimming test (FST), and novelty suppressed-feeding test (NSFT) were performed in sequence on mice after GJ-IF administration. 2. Mice in the model group were under chronic unpredictable mild stress (CUMS) for 3 w. After GJ-IF treatment, mice were placed in an open field test (OFT), Sucrose preference test (SPT), NSFT, TST, and FST. 3. Western Blot was performed to examine the expression of brain-derived neurotrophic factor (BDNF), Synapsin 1, cyclic-AMP dependent protein kinase A (PKA), phosphorylated cyclic-AMP responsive element-binding protein (p-CREB), and cAMP response element-binding protein (CREB). 4. Mice in the test group were administrated with GJ-IF after intraperitoneal injection of PKA blocker H89. Results: 1. GJ-IF treatment significantly reduced the immobility time of TST at 1 d and FST at 26 h. 2. GJ-IF reversed the deficits induced by 3 w CUMS in SPT, TST, FST, and NSFT at 1 d and 26 h. The antidepressant effects of a single dose of iridoid fraction could also last for at least 14 d. 3. The results of molecule studies suggested that a single dose of GJ-IF activated p-CREB at 2 h and the PKA-CREB pathway at 1 d. The expression of BDNF did not significantly change from 30 min to 1 d after GJ-IF administration. 4. Blockade of PKA-CREB signaling pathway reversed the antidepressant effects of GJ-IF at 1 d, but not 30 min and 2 h. Conclusion: GJ-IF is the crucial component in the rapid antidepressant of GJ. Rapid and sustained antidepressant effects of GJ-IF were dependent on activating the PKA-CREB signaling pathway.

Keywords: BDNF; CREB; Gardenia jasminoides Ellis; PKA; iridoid fraction; rapid and enduring antidepressant.