Pemafibrate treatment produces antidepressant-like effects in CUMS and CRS models through activation of hippocampal PPARα and BDNF signaling

Aug 30, 2025The international journal of neuropsychopharmacology

Pemafibrate may reduce depression-like symptoms in stress models by activating brain pathways linked to mood and memory

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Abstract

Pemafibrate significantly ameliorated chronic stress-induced depressive-like behaviors in mouse models.

Repeated administration of pemafibrate restored hippocampal PPARα levels, signaling, and neurogenesis.
Antidepressant effects were diminished when co-administered with PPARα or BDNF signaling inhibitors.
Genetic knockdown of hippocampal PPARα or BDNF eliminated the antidepressant-like actions of pemafibrate.
Findings suggest that pemafibrate may enhance antidepressant efficacy through modulation of specific neurobiological pathways.

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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 () 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.

Key numbers

28.9±3.92%

Decrease in Immobility (FST)

Compared to CUMS controls after 0.3 mg/kg pemafibrate treatment.

30±5.35%

Increase in Sucrose Preference

In CUMS-treated mice following pemafibrate administration.

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Pemafibrate treatment produces antidepressant-like effects in CUMS and CRS models through activation of hippocampal PPARα and BDNF signaling

Abstract

Key numbers

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