Abstract
BACKGROUND: It is well established that peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the pathogenesis of depression. Several PPARα agonists, including WY14643, fenofibrate, and gemfibrozil, have been reported to produce antidepressant-like effects in mouse models through PPARα-mediated enhancement of hippocampal brain-derived neurotrophic factor (BDNF) signaling and neurogenesis. Pemafibrate is a novel and highly selective modulator of PPARα; we therefore hypothesized that it might also exhibit antidepressant-like efficacy. METHODS: We employed 2 established mouse models of depression, chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS), to evaluate the potential antidepressant effects of pemafibrate. Western blotting and immunofluorescence were used to assess whether pemafibrate treatment counteracts chronic stress-induced suppression of hippocampal PPARα, BDNF signaling, and neurogenesis. To investigate the mechanism of action, we utilized pharmacological inhibitors (GW6471 for PPARα and K252a for BDNF signaling) combined with adeno-associated virus-mediated genetic knockdown approaches. RESULTS: Repeated pemafibrate administration significantly ameliorated chronic stress-induced depressive-like behaviors and restored hippocampal PPARα levels, BDNF signaling, and neurogenesis in both models. These antidepressant effects were markedly attenuated by co-administration of GW6471 or K252a. Similarly, genetic knockdown of either hippocampal PPARα or BDNF abolished pemafibrate's antidepressant-like actions. CONCLUSIONS: Pemafibrate exerts antidepressant-like effects in both CUMS and CRS mouse models by promoting hippocampal PPARα and BDNF signaling.