Administration of chiglitazar reverses chronic stress-induced depressive-like symptoms in mice via activation of hippocampal PPARα and BDNF.

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.