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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1587399
Administration of chiglitazar reverses chronic stress-induced depressive-like symptoms in mice via activation of hippocampal PPARα and BDNF
Provisionally accepted- Sixth People's Hospital of Nantong, Nantong, China
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Background: Developing non-monoamine based novel antidepressants is now popular and necessary. Peroxisome proliferator-activated receptor α (PPARα) has been demonstrated to play a role in the pathophysiology of depression, and several PPARα agonists including WY14643, fenofibrate, and gemfibrozil, have all been reported to possess antidepressant-like efficacy in rodents. Chiglitazar is a novel pan agonist of PPARs, and this study aims to investigate whether this agonist has beneficial effects against depression. Methods: Chronic unpredictable mild stress (CUMS), chronic restraint stress (CRS), forced swim test (FST), tail suspension test (TST), sucrose preference test (SPT), western blotting, and adeno-associated virus (AAV)-mediated gene transfer were adopted together in the present study. Results: It was found that repeated intraperitoneal (i.p.) injection of chiglitazar significantly reversed both CUMS-induced and CRS-induced depressive-like behaviors in mice in the FST, TST, and SPT. Chiglitazar treatment also fully reversed both CUMS-induced and CRS-induced downregulation in the expression of hippocampal PPARα and brain-derived neurotrophic factor (BDNF) signaling in mice. Furthermore, pharmacological blockade of hippocampal PPARα and BDNF signaling attenuated the antidepressant-like effects of chiglitazar in mice. Genetic knockdown of hippocampal PPARα and BDNF also abolished the antidepressant-like actions of chiglitazar in mice. Conclusion: In summary, administration of chiglitazar reverses chronic stress-induced depressive-like symptoms in mice via activation of hippocampal PPARα and BDNF.
Keywords: Brain-Derived Neurotrophic Factor, Chiglitazar, chronic stress, Depression, Hippocampus, Peroxisome proliferator-activated receptor α
Received: 04 Mar 2025; Accepted: 16 Apr 2025.
Copyright: © 2025 Zhou, Zhao, Gao, Gao, Chen, Ding, Wu and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Zhonghua Wu, Sixth People's Hospital of Nantong, Nantong, China
Pu-jian Chen, Sixth People's Hospital of Nantong, Nantong, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.