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

Jin Zhou; Wei Zhao; Hua Fan; Si-Yi Zhou; Xiao-Li Zhang; Hui Xu; Bo Jiang; Wei Liu; Zhi-Ming Cui; Da-Wei Xu

doi:10.1093/ijnp/pyaf063

. 2025 Aug 30;28(9):pyaf063. doi: 10.1093/ijnp/pyaf063

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

Jin Zhou ^1,^#, Wei Zhao ^2,^#, Hua Fan ^3,^#, Si-Yi Zhou ⁴, Xiao-Li Zhang ⁵, Hui Xu ⁶, Bo Jiang ⁷, Wei Liu ⁸, Zhi-Ming Cui ⁹, Da-Wei Xu ^10,^✉

¹ Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China

² Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China

³ The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, Henan, China

⁴ Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China

⁵ Department of Rheumatology and Immunology, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China

⁶ Department of Neurosurgery, Nantong Hospital of Traditional Chinese Medicine, Nantong 226009, Jiangsu, China

⁷ Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China

⁸ Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China

⁹ Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China

¹⁰ Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China

^✉

Corresponding author: Da-Wei Xu, PhD, Department of Orthopedics, Affiliated Hospital 2 of Nantong University, 666 Shengli Road, Nantong 226000, Jiangsu, China (xdw_nt1y@163.com)

Author Contributions: Jin Zhou, Wei Zhao and Hua Fan contributed equally to this work.

Roles

Jin Zhou: MSc, Methodology, Writing - original draft

Wei Zhao: MSc, Methodology, Writing - original draft

Hua Fan: PhD, Methodology

Si-Yi Zhou: MSc, Methodology

Xiao-Li Zhang: MSc, Methodology

Hui Xu: PhD, Methodology

Bo Jiang: PhD, Conceptualization, Formal analysis, Investigation, Resources, Supervision, Visualization, Writing - review & editing

Wei Liu: PhD, Methodology

Zhi-Ming Cui: PhD, Conceptualization, Formal analysis, Funding acquisition, Investigation, Project administration, Resources, Supervision, Visualization, Writing - review & editing

Da-Wei Xu: PhD, Conceptualization, Formal analysis, Funding acquisition, Investigation, Project administration, Resources, Supervision, Visualization, Writing - review & editing

PMCID: PMC12452276 PMID: 40884470

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.

Keywords: brain-derived neurotrophic factor, chronic stress, depression, hippocampus, pemafibrate, peroxisome proliferator-activated receptor α

Highlights

Pemafibrate administration reversed the pro-depressant effects of both CUMS and CRS on mouse behaviors.
Pemafibrate administration reversed the inhibitory effects of both CUMS and CRS on hippocampal PPARα, BDNF signaling, and neurogenesis in mice.
The antidepressant-like effects of pemafibrate in the CUMS model were mediated by both hippocampal PPARα and BDNF.
The antidepressant-like actions of pemafibrate in the CRS model were mediated by both hippocampal PPARα and BDNF.

INTRODUCTION

It is widely known that depression is a serious, frequently occurring, and highly debilitating neuropsychiatric disorder worldwide. In clinical practice, it is characterized by many symptoms, such as anhedonia, social avoidance, insomnia, decreased appetite, and desperate mood.^1–6 Despite decades of research, the exact pathogenesis of depression remains elusive and not fully understood.²^,⁷^,⁸ Currently, most antidepressants used in clinical practice (e.g., fluoxetine, paroxetine, venlafaxine, duloxetine) are developed based on the monoaminergic theory, which postulates that decreased synaptic concentrations of serotonin (5-HT) and norepinephrine (NA) contribute to many symptoms of depression.⁷^,⁸ Although these monoamine-based antidepressants can alleviate depression, they have a relatively low response (less than 70%) and a high relapse rates (up to 40%).^9–11 Moreover, their delayed onset of action is another limitation.^9–11 Therefore, exploring more effective and reliable antidepressants is necessary.

Beyond the monoamine hypothesis, the neurotrophic hypothesis of depression is also well-known and widely accepted.⁷^,⁸^,^12–14 This hypothesis postulates that both brain-derived neurotrophic factor (BDNF) and its downstream molecule, cAMP response element-binding protein (CREB), play critical roles in the pathogenesis of depression.⁷^,⁸^,^13–16 Numerous studies have demonstrated that in mouse models of depression, chronic stress significantly downregulates hippocampal BDNF expression and CREB activity, whereas treatment with monoamine-based antidepressants, such as fluoxetine, fully reverses these changes.⁷^,⁸^,¹⁵^,¹⁷^,¹⁸ Similarly, decreased level of BDNF have also been observed in the postmortem hippocampus of individuals with depression.⁷^,⁸^,¹⁵ Moreover, compared with naïve control mice, genetic knockout of BDNF or CREB increases susceptibility to chronic stress.¹⁹ Furthermore, direct infusion of BDNF or CREB into the hippocampus produces notable antidepressant-like effects in rodent models of depression.²⁰ Regarding the biological relationship between BDNF and CREB, it is well-established that BDNF induces ser-133 phosphorylation of nuclear CREB by binding to membrane tyrosine kinase B (TrkB) and subsequently activating cytoplasmic extracellular signal-regulated kinase (ERK) and protein kinase B (AKT).^21–23

Pemafibrate, developed by Kowa Company, Ltd., is a novel and highly selective modulator of peroxisome proliferator-activated receptor α (PPARα).²⁴^,²⁵ Pemafibrate acts by binding to PPARα and regulating the expression of target genes involved in lipid metabolism.²⁵ Interestingly, while peripheral PPARα regulates lipid metabolism, central PPARα plays a role in numerous neurological and psychiatric disorders, including depression.^26–29 For example, a previous study has demonstrated that hippocampal PPARα (but not PPARα in other depression-related brain regions) is modulated by both chronic stress and fluoxetine treatment.³⁰ Genetic overexpression of hippocampal PPARα prevented chronic stress–induced depression in mice, whereas knockdown of PPARα exacerbated these effects. These changes were mediated through regulation of BDNF biosynthesis and CREB activity in the hippocampus.³⁰ Notably, 2 other fibrates, fenofibrate and gemfibrozil, produced significant antidepressant-like effects in mouse models of depression by enhancing PPARα-mediated BDNF biosynthesis in the hippocampus.³¹^,³² Similarly, WY14643, another selective PPARα agonist, has been shown to protect against chronic stress in rodents.³³ Based on these findings, we hypothesized that pemafibrate, like fenofibrate, gemfibrozil, and WY14643, might possess antidepressant-like properties. In this study, we employed multiple approaches to investigate this possibility.

MATERIALS AND METHODS

Ethics Statements

All animal procedures adhered to the ARRIVE guidelines³⁴^,³⁵ and were approved by the Animal Welfare Committee of Nantong University.

Animals

This study utilized 8-week-old male C57BL/6 J mice (weighing 22-24 g) as experimental subjects, which were purchased from Shanghai SLAC Laboratory Animal Co., Ltd. Prior to the experiment, all mice were acclimatized in our facility for 1 week under the following housing conditions: group-housed with 5 mice per cage; 12-hour-light/-dark cycle (lights on from 6:00 am to 6:00 pm); ambient temperature of (24 ± 1)°C; relative humidity of (55 ± 10)%; noise levels below 50 dB; ammonia concentration below 14 mg/m³; 24-hour air circulation; and bedding replaced twice a week. These conditions were consistent with previous studies.³⁰^,³⁶^,³⁷ Subsequently, the mice were subjected to stratified randomization according to body weight. All behavioral tests were conducted during the daytime (8:00 am to 5:00 pm). For the in vitro studies, animals were randomly selected and killed at 9:00 am using a standard method (anesthetized with carbon dioxide followed by cervical dislocation). The sample sizes (in vivo, n = 10; in vitro, n = 5) were determined by power analysis and based on previous studies.³⁰^,³⁶^,³⁷

Drugs

MedChemExpress (Monmouth Junction, USA) provided pemafibrate (vehicle: 5% dextrose [pH 7.0] + 2.5% DMSO +10% Cremophor EL). Target Mol (Boston, USA) provided fluoxetine (vehicle: 5% dextrose [pH 7.0] + 2.5% DMSO +10% Cremophor EL), K252a (vehicle: 5% dextrose [pH 7.]) + 2.5% DMSO +10% Cremophor EL), and GW6471 (vehicle: 5% dextrose [pH 7.0] + 2.5% DMSO +10% Cremophor EL). According to previous studies,³⁰^,³¹^,³³^,^38–41 the doses of these compounds were determined as following: pemafibrate (0.1 and 0.3 mg/kg), fluoxetine (20 mg/kg), K252a (25 μg/kg), and GW6471 (1 mg/kg). All these compounds were intraperitoneally (i.p.) injected at a volume of 10 mL/kg.

Forced Swim Test (FST)

This test is performed according to a protocol frequently described in previous reports.^31–33 In the FST, each mouse was individually placed into a transparent cylindrical container provided by XinRuan Technology Co., Ltd. (Shanghai, China), with a diameter of 20 cm and a height of 45 cm. The mice were required to swim continuously for 6 minutes in pure water filled to a depth of 20 cm, maintained at a temperature of 24 ± 1°C. The water was replaced after each trial. During the final 4 minutes of the test, an investigator blinded to the animal groupings recorded the immobility time of each mouse. Immobility was defined as the mouse being completely motionless or exhibiting only minor movements necessary to maintain breathing.

Tail Suspension Test (TST)

This test is performed according to a protocol frequently described in previous reports.^31–33 In the TST, each test mouse was secured with adhesive tape 1 cm from the tip of its tail and suspended 70 cm above the ground. The test duration was 6 minutes, during which an investigator blinded to the animal groupings recorded the immobility time of each mouse. Immobility was defined as the state in which the mouse remained completely motionless. To prevent potential climbing behaviors during the test, transparent hollow anti-climbing tubes (1.5 cm in diameter, 4 cm in length) provided by XinRuan Technology Co., Ltd. were used.

Sucrose Preference Test (SPT)

This test is performed according to a protocol frequently described in previous reports.^31–33 In the SPT, each test mouse was individually housed and acclimated to 2 identical bottles, one containing a 1% sucrose solution and the other containing pure water, for a period of 48 hours. To prevent the mice from developing a preference for a specific position, the locations of the 2 bottles were switched every 12 hours. Following this, the mice underwent 18 hours of food and water deprivation, after which the pre-weighed bottles were returned, and the mice were allowed to drink freely for 3 hours (with the bottle positions switched every 1 hour). After the experiment, the bottles were weighed again. The sucrose preference index for each mouse was calculated as a percentage using the formula 100 × volume of sucrose consumed/total volume consumed.

Statistical Analysis

The experimental data are presented as mean ± SEM. For statistical analysis, SPSS 22.0 software (SPSS Inc., Chicago, USA) was used, with 1-way ANOVA combined with Tukey test and 2-way ANOVA combined with Bonferroni’ test. The statistical significance level was set at P < .05 (2-tailed).

Additional Methods and Materials

See the Supplemental Methods and Materials for description of chronic unpredictable mild stress (CUMS), chronic restraint stress (CRS), adeno-associated virus (AAV)-mediated gene transfer, western blotting, and immunofluorescence.

RESULTS

Pemafibrate Treatment Significantly Reversed Both CUMS-Induced and CRS-Induced Depressive-like Behaviors in Mice

The antidepressant-like effects of pemafibrate were evaluated using both the CUMS and CRS models of depression, as these are well-established in depression research.^42–44

Figure 1 summarizes the behavioral results for the CUMS-related experiments. Compared with mice in the control group, CUMS exposure significantly increased mouse immobility in the FST and TST by 57.9 ± 6.63% and 60.5 ± 5.38%, respectively, and notably decreased the sucrose preference of mice by 40.8 ± 4.51% (n = 10, P < .01). In contrast, repeated administration of 0.1 mg/kg pemafibrate reduced the immobility of CUMS-treated mice in the FST and TST by 24.6 ± 4.19% and 28.9 ± 3.92%, respectively, and enhanced the sucrose preference of CUMS-treated mice by 30 ± 5.35% (n = 10, P < .01). Repeated administration of 0.3 mg/kg pemafibrate achieved better efficacy, especially in the TST and SPT, and the amplitude of 0.3 mg/kg pemafibrate-induced effects were comparable with that of 20 mg/kg fluoxetine, the positive control (n = 10, P < .01). Moreover, fluoxetine treatment also decreased the immobility of naïve control mice in the FST and TST, whereas pemafibrate treatment did not (n = 10, P < .01). For the FST data, 2-way ANOVA revealed a significant interaction [F_(3,72) = 13.782, P < .01], with notable effects for CUMS [F_(1,72) = 24.187, P < .01] and drug treatment [F_(3,72) = 18.249, P < .01]. For the TST data, 2-way ANOVA showed a significant interaction [F_(3,72) = 16.223, P < .01], with notable effects for CUMS [F_(1,72) = 32.076, P < .01] and drug treatment [F_(3,72) = 23.194, P < .01]. For the SPT data, 2-way ANOVA also reported a significant interaction [F_(3,72) = 12.646, P < .01], with notable effects for CUMS [F(1,72) = 25.714, P < .01] and drug treatment [F_(3,72) = 17.658, P < .01].

Male C57BL/6 J mice were subjected to 8 weeks of CUMS, and intraperitoneal (i.p.) injection of 20 mg/kg fluoxetine, 0.1 mg/kg pemafibrate, 0.3 mg/kg pemafibrate, or vehicle was performed daily during the last 2 weeks. A schematic timeline for the experimental procedures is shown in (A). Repeated injection of 20 mg/kg fluoxetine, 0.1 mg/kg pemafibrate, and 0.3 mg/kg pemafibrate significantly reversed CUMS-induced depressive-like behaviors in the FST (B), TST (C), and SPT (D). All data are presented as means ± SEM (n = 10); ^**P < .01. n.s., no significance. The comparisons were made by 2-way ANOVA followed by Bonferroni test.

Figure 2 summarizes the behavioral results for the CRS-related experiments. Similar to CUMS, compared with mice in the control group, CRS exposure increased mouse immobility in the FST and TST by 48.5 ± 4.73% and 63.9 ± 7.56%, respectively, and decreased the sucrose preference of mice by 37.5 ± 5.42% (n = 10, P < .01). Repeated treatment of 20 mg/kg fluoxetine, 0.1 mg/kg pemafibrate, and 0.3 mg/kg pemafibrate fully reversed CRS-induced behavioral changes in the FST, TST, and SPT (n = 10, P < .01). For the FST data, 2-way ANOVA revealed a significant interaction [F_(3,72) = 11.448, P < .01], with notable effects for CRS [F_(1,72) = 21.885, P < .01] and drug treatment [F_(3,72) = 15.622, P < .01]. For the TST data, 2-way ANOVA showed a significant interaction [F_(3,72) = 14.547, P < .01], with notable effects for CRS [F_(1,72) = 30.805, P < .01] and drug treatment [F_(3,72) = 22.625, P < .01]. For the SPT data, 2-way ANOVA also reported a significant interaction [F_(3,72) = 9.339, P < .01], with notable effects for CRS [F_(1,72) = 19.778, P < .01] and drug treatment [F_(3,72) = 14.289, P < .01].

Male C57BL/6 J mice were subjected to 8 weeks of CRS, and i.p. injection of 20 mg/kg fluoxetine, 0.1 mg/kg pemafibrate, 0.3 mg/kg pemafibrate, or vehicle was performed daily during the last 2 weeks. A schematic timeline for the experimental procedures is shown in (A). Repeated injection of 20 mg/kg fluoxetine, 0.1 mg/kg pemafibrate, and 0.3 mg/kg pemafibrate significantly reversed CRS-induced depressive-like behaviors in the FST (B), TST (C), and SPT (D). All data are presented as means ± SEM (n = 10); ^**P < .01. n.s., no significance. The comparisons were made by 2-way ANOVA followed by Bonferroni test.

Collectively, these findings indicate that pemafibrate has the potential of being an antidepressant.

Pemafibrate Administration Notably Reversed Both CUMS-Induced and CRS-Induced Decrease in Hippocampal PPAR Expression, BDNF Signaling, and Neurogenesis in Mice

Afterwards, western blotting was performed to examine the levels of hippocampal PPARα and BDNF signaling across all experimental groups. Immunofluorescence was additionally performed to detect the level of hippocampal neurogenesis.

Figure 3 shows the western blotting data for the CUMS-related experiments. Compared with mice in the control group, CUMS exposure evidently decreased the expression of hippocampal PPARα [2-way ANOVA: CUMS, F_(1,16) = 35.126, P < .01; drug treatment, F_(1,16) = 27.509, P < .01; interaction, F_(1,16) = 19.864, P < .01], BDNF [2-way ANOVA: CUMS, F_(1,16) = 25.648, P < .01; drug treatment, F_(1,16) = 18.701, P < .01; interaction, F_(1,16) = 15.332, P < .01], pTrkB [2-way ANOVA: CUMS, F_(1,16) = 27.149, P < .01; drug treatment, F_(1,16) = 21.608, P < .01; interaction, F_(1,16) = 13.447, P < .01], pAKT [2-way ANOVA: CUMS, F_(1,16) = 23.154, P < .01; drug treatment, F_(1,16) = 16.571, P < .01; interaction, F_(1,16) = 12.279, P < .01], pERK1/2 [2-way ANOVA: CUMS, F_(1,16) = 18.681, P < .01; drug treatment, F_(1,16) = 14.755, P < .01; interaction, F_(1,16) = 10.919, P < .01], and pCREB [2-way ANOVA: CUMS, F_(1,16) = 32.143, P < .01; drug treatment, F_(1,16) = 24.475, P < .01; interaction, F_(1,16) = 16.091, P < .01] in mice (n = 5, P < .01). In contrast, treatment with 0.3 mg/kg pemafibrate significantly increased the expression of these molecules in CUMS-exposed mice (n = 5, P < .01). Figure 4 shows the western blotting data for the CRS-related experiments. Similar to CUMS, compared with mice in the control group, CRS exposure notably decreased the expression of hippocampal PPARα [2-way ANOVA: CRS, F_(1,16) = 38.474, P < .01; drug treatment, F_(1,16) = 28.779, P < .01; interaction, F_(1,16) = 22.663, P < .01], BDNF [2-way ANOVA: CRS, F_(1,16) = 31.569, P < .01; drug treatment, F_(1,16) = 23.402, P < .01; interaction, F_(1,16) = 17.115, P < .01], pTrkB [2-way ANOVA: CRS, F_(1,16) = 25.373, P < .01; drug treatment, F_(1,16) = 16.098, P < .01; interaction, F_(1,16) = 12.883, P < .01], pAKT [2-way ANOVA: CRS, F_(1,16) = 30.637, P < .01; drug treatment, F_(1,16) = 22.359, P < .01; interaction, F_(1,16) = 15.721, P < .01], pERK1/2 [2-way ANOVA: CRS, F_(1,16) = 17.199, P < .01; drug treatment, F_(1,16) = 13.286, P < .01; interaction, F_(1,16) = 9.565, P < .01], and pCREB [2-way ANOVA: CRS, F_(1,16) = 34.007, P < .01; drug treatment, F_(1,16) = 26.204, P < .01; interaction, F_(1,16) = 18.815, P < .01] in mice, and these molecular changes were significantly reversed by administration of 0.3 mg/kg pemafibrate (n = 5, P < .01). The expression of total TrkB, AKT, ERK1/2, and CREB did not change across all groups (n = 5).

Representative western blotting images (A) and corresponding data analyses (B) together show the effects of CUMS and 0.3 mg/kg pemafibrate on the protein expression of PPARα, BDNF, pTrkB, TrkB, pAKT, AKT, pERK1/2, ERK1/2, pCREB, and CREB in the hippocampus of male C57BL/6 J mice. All data are presented as means ± SEM (n = 5); ^**P < .01. n.s., no significance. The comparisons were made by 2-way ANOVA followed by Bonferroni test.

Representative western blotting images (A) and corresponding data analyses (B) together show the effects of CRS and 0.3 mg/kg pemafibrate on the protein expression of PPARα, BDNF, pTrkB, TrkB, pAKT, AKT, pERK1/2, ERK1/2, pCREB, and CREB in the hippocampus of male C57BL/6 J mice. All data are presented as means ± SEM (n = 5); ^**P < .01. n.s., no significance. The comparisons were made by 2-way ANOVA followed by Bonferroni test.

Previous studies have established that both BDNF and CREB regulates hippocampal neurogenesis, a critical process for brain development, neuronal maintenance, and synaptic plasticity.⁴⁵^,⁴⁶ Importantly, as well as BDNF and CREB, hippocampal neurogenesis is also closely implicated in the pathophysiology of depression.^47–50 We therefore investigated pemafibrate’s effects on chronic stress-induced neurogenesis alterations using doublecortin (DCX) immunohistochemistry in the dentate gyrus (DG).³¹^,³³^,⁵¹ As shown in Figures 5 and 6, compared with mice in the control group, exposure to CUMS and CRS reduced the number of DCX-positive cells in the DG of mice by 79.6 ± 8.55% and 75.8 ± 9.34%, respectively, and these biological changes were fully reversed by injection of 0.3 mg/kg pemafibrate (n = 5, P < .01). For Figure 5, 2-way ANOVA revealed a significant interaction [F_(1,16) = 24.398, P < .01], with notable effects for CUMS [F_(1,16) = 57.94, P < .011] and drug treatment [F_(1,16) = 36.485, P < .01]. For Figure 6, 2-way ANOVA also reported a significant interaction [F_(1,16) = 32.604, P < .01], with notable effects for CRS [F_(1,16) = 62.103, P < .01] and drug treatment [F_(1,16) = 41.285, P < .01].

Representative immunofluorescence images and corresponding data analyses together reveal the effects of CUMS and 0.3 mg/kg pemafibrate on DCX⁺ cell numbers in the DG region of male C57BL/6 J mice. The scale bars for representative and enlarged images are 150 and 37.5 μm, respectively. All data are presented as means ± SEM (n = 5); ^**P < .01. n.s., no significance. The comparisons were made by 2-way ANOVA followed by Bonferroni test.

Representative immunofluorescence images and corresponding data analyses together reveal the effects of CRS and 0.3 mg/kg pemafibrate on DCX⁺ cell numbers in the DG region of male C57BL/6 J mice. The scale bars for representative and enlarged images are 150 and 37.5 μm, respectively. All data are presented as means ± SEM (n = 5); ^**P < .01. n.s., no significance. The comparisons were made by 2-way ANOVA followed by Bonferroni test.

Collectively, these results suggest that pemafibrate may produce antidepressant-like effects in mice by enhancing hippocampal PPARα and BDNF signaling.

Pharmacological Blockade of Hippocampal PPAR and BDNF Signaling Attenuated the Antidepressant-like Effects of Pemafibrate in Mice

Furthermore, to determine whether hippocampal PPARα and BDNF signaling are indeed necessary for the antidepressant-like effects of pemafibrate in mice, we co-administered GW6471 (a PPARα antagonist) or K252a (a TrkB antagonist) with pemafibrate. Figure 7A shows that combined treatment with GW6471 or K252a significantly attenuated the antidepressant-like effects of pemafibrate in the CUMS model (n = 10, P < .01), as the (CUMS + pemafibrate)-treated mice displayed significantly lower immobility in the FST [1-way ANOVA: F_(6,63) = 22.672, P < .01] and TST [1-way ANOVA: F_(6,63) = 25.439, P < .01] as well as higher sucrose preference [1-way ANOVA: F_(6,63) = 15.321, P < .01] than both the (CUMS + pemafibrate + GW6471)-treated and (CUMS + pemafibrate + K252a)-treated mice. Figure 7B shows that combined treatment with GW6471 or K252a evidently blocked the antidepressant-like effects of pemafibrate in the CRS model (n = 10, P < .01), as the (CRS + pemafibrate)-treated mice had evidently less immobility in the FST [1-way ANOVA: F_(6,63) = 23.065, P < .01] and TST [1-way ANOVA: F_(6,3) = 27.308, P < .01] as well as more sucrose preference [1-way ANOVA: F_(6,63) = 16.412, P < .01] than both the (CRS + pemafibrate + GW6471)-treated and (CRS + pemafibrate + K252a)-treated mice.

Male C57BL/6 J mice were subjected to 8 weeks of CUMS or CRS, and i.p. injection of vehicle, 1 mg/kg GW6471, 25 μg/kg K252a, 0.3 mg/kg pemafibrate, (0.3 mg/kg pemafibrate +1 mg/kg GW6471), or (0.3 mg/kg pemafibrate +25 μg/kg K252a) was performed daily during the last 2 weeks. (A) the usage of both 1 mg/kg GW6471 and 25 μg/kg K252a significantly attenuated the reversal effects of 0.3 mg/kg pemafibrate against CUMS-induced depressive-like behaviors in the FST, TST, and SPT. A schematic timeline of experimental procedures is provided. (B) the usage of both 1 mg/kg GW6471 and 25 μg/kg K252a notably blocked the reversal effects of 0.3 mg/kg pemafibrate against CRS-induced depressive-like behaviors in the FST, TST, and SPT. A schematic timeline of experimental procedures is provided. All data are presented as means ± SEM (n = 10); ^**P < .01. n.s., no significance. The comparisons were made by 1-way ANOVA followed by Tukey test.

Genetic Knockdown of Hippocampal PPARα and BDNF Abolished the Antidepressant-like Effects of Pemafibrate in Mice

To address potential nonspecific effects of pharmacological antagonists, AAV-PPARα-short hairpin RNA (shRNA)-enhanced green fluorescent protein (EGFP) and AAV-BDNF-shRNA-EGFP were used to selectively knockdown the expression of hippocampal PPARα and BDNF, respectively, in mice. As shown in Figure 8A and B, the silencing efficacy of PPARα-shRNA [1-way ANOVA: F_(2,12) = 37.118, P < .01] and BDNF-shRNA [1-way ANOVA: F_(2,12) = 25.967, P < .01] have been confirmed (n = 5, P < .01). Moreover, Figure 8C and D show that the usage of PPARα-shRNA and BDNF-shRNA produced none influence on behaviors of naïve control mice in the FST [1-way ANOVA for PPARα-shRNA: F_(2,27) = 1.265, P < .05; 1-way ANOVA for BDNF-shRNA: F_(2,27) = 1.439, P < .05], TST [1-way ANOVA for PPARα-shRNA: F_(2,27) = 1.508, P < .05; 1-way ANOVA for BDNF-shRNA: F_(2,27) = 1.746, P < .05], and SPT [1-way ANOVA for PPARα-shRNA: F_(2,27) = 0.781, P < .05; 1-way ANOVA for BDNF-shRNA: F_(2,27) = 0.954, P < .05] (n = 10).

The fluorescence images of a fixed hippocampal slice expressing AAV-PPARα-shRNA-EGFP (A) or AAV-BDNF-shRNA-EGFP (B), and the scale bars for representative and enlarged images are 400 and 50 μm, respectively. Two weeks were required for AAV-PPARα-shRNA-EGFP and AAV-BDNF-shRNA-EGFP to spread over the whole hippocampus of mice. The following western blotting results confirmed the silencing effects of PPARα-shRNA (A) and BDNF-shRNA (B) on the protein expression of hippocampal PPARα and BDNF in mice, respectively. Neither PPARα-shRNA (C) nor BDNF-shRNA (D) treatment affected behavioral performance of naïve control mice in the FST, TST, or SPT. All data are presented as means ± SEM [n = 5 for (A) and (B); n = 10 for (C) and (D)]; ^**P < .01. n.s., no significance. The comparisons were made by 1-way ANOVA followed by Tukey test.

Figure 9A shows that pretreatment with PPARα-shRNA significantly abolished the antidepressant-like effects of pemafibrate in the CUMS model (n = 10, P < .01). Detailed analyses reveal that the (CUMS + pemafibrate)-treated and (CUMS + pemafibrate + Control-shRNA)-treated mice displayed 20.8 ± 3.84% and 21.9 ± 2.67% lower immobility in the FST, respectively, than the (CUMS + pemafibrate + PPARα-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 21.996, P < .01]. The (CUMS + pemafibrate)-treated and (CUMS + pemafibrate + control-shRNA)-treated mice also exhibited 21.8 ± 3.75% and 26.1 ± 4.83% lower immobility in the TST, respectively, than the (CUMS + pemafibrate + PPARα-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 24.355, P < .01]. Moreover, the (CUMS + pemafibrate)-treated and (CUMS + pemafibrate + control-shRNA)-treated mice had 28.7 ± 2.89% and 26.3 ± 4.37% higher sucrose preference, respectively, than the (CUMS + pemafibrate + PPARα-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 14.801, P < .01]. Figure 9B reveals that pretreatment of PPARα-shRNA notably abrogated the antidepressant-like effects of pemafibrate in the CRS model of depression (n = 10, P < .01). Detailed analyses reveal that the (CRS + pemafibrate)-treated and (CRS + pemafibrate + control-shRNA)-treated mice displayed 28.6 ± 3.94% and 26.6 ± 4.17% less immobility in the FST, respectively, than the (CRS + pemafibrate + PPARα-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 24.505, P < .01]. The (CRS + pemafibrate)-treated and (CRS + pemafibrate + control-shRNA)-treated mice also exhibited 24.3 ± 4.04% and 26.2 ± 3.59% less immobility in the TST, respectively, than the (CRS + pemafibrate + PPARα-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 28.661, P < .01]. In addition, the (CRS + pemafibrate)-treated and (CRS + pemafibrate + control-shRNA)-treated mice had 39.3 ± 4.76% and 35.5 ± 5.28% more sucrose preference, respectively, than the (CRS + pemafibrate + PPARα-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 18.346, P < .01].

Male C57BL/6 J mice were subjected to stereotactic infusion of PPARα-shRNA or control-shRNA first and then 8 weeks of CUMS or CRS, followed by daily injection of 0.3 mg/kg pemafibrate or vehicle during the last 2 weeks. (A) Pretreatment with PPARα-shRNA, but not control-shRNA, significantly abolished the reversal effects of 0.3 mg/kg pemafibrate against CUMS-induced depressive-like behaviors in the FST, TST, and SPT. A schematic timeline of the experimental procedures is provided. (B) Pretreatment of PPARα-shRNA, but not control-shRNA, notably abrogated the reversal effects of 0.3 mg/kg pemafibrate against CRS-induced depressive-like behaviors in the FST, TST, and SPT. A schematic timeline of experimental procedures is provided. All data are presented as means ± SEM (n = 10); ^**P < .01. n.s., no significance. The comparisons were made by 1-way ANOVA followed by Tukey test.

Similarly, Figure 10A shows that pretreatment with BDNF-shRNA significantly abolished the antidepressant-like effects of pemafibrate in the CUMS model (n = 10, P < .01). Detailed analyses reveal that the (CUMS + pemafibrate)-treated and (CUMS + pemafibrate + control-shRNA)-treated mice displayed 22.4 ± 1.89% and 21 ± 2.32% lower immobility in the FST, respectively, than the (CUMS + pemafibrate + BDNF-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 20.554, P < .01]. The (CUMS + pemafibrate)-treated and (CUMS + pemafibrate + control-shRNA)-treated mice also exhibited 25.1 ± 3.36% and 23.3 ± 1.76% lower immobility in the TST, respectively, than the (CUMS + pemafibrate + BDNF-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 26.974, P < .01]. Moreover, the (CUMS + pemafibrate)-treated and (CUMS + pemafibrate + control-shRNA)-treated mice had 33.7 ± 5.54% and 26.3 ± 4.81% higher sucrose preference, respectively, than the (CUMS + pemafibrate + BDNF-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 16.004, P < .01]. Figure 10B reveals that pretreatment of BDNF-shRNA also notably abrogated the antidepressant-like effects of pemafibrate in the CRS model (n = 10, P < .01). Detailed analyses revealed that the (CRS + pemafibrate)-treated and (CRS + pemafibrate + control-shRNA)-treated mice displayed 20.7 ± 2.29% and 18 ± 1.56% less immobility in the FST, respectively, than the (CRS + pemafibrate + BDNF-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 19.564, P < .01]. The (CRS + pemafibrate)-treated and (CRS + pemafibrate + control-shRNA)-treated mice also exhibited 26.9 ± 4.43% and 23.1 ± 3.05% less immobility in the TST, respectively, than the (CRS + pemafibrate + BDNF-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 23.094, P < .01]. In addition, the (CRS + pemafibrate)-treated and (CRS + pemafibrate + control-shRNA)-treated mice had 44.9 ± 6.37% and 42 ± 5.82% more sucrose preference, respectively, than the (CRS + pemafibrate + BDNF-shRNA)-treated mice [1-way ANOVA: F_(6,63) = 13.078, P < .01].

Male C57BL/6 J mice were subjected to stereotactic infusion of BDNF-shRNA or control-shRNA first and then 8 weeks of CUMS or CRS, followed by daily injection of 0.3 mg/kg pemafibrate or vehicle during the last 2 weeks. (A) Pretreatment with BDNF-shRNA, but not control-shRNA, significantly abolished the reversal effects of 0.3 mg/kg pemafibrate against CUMS-induced depressive-like behaviors in the FST, TST, and SPT. A schematic timeline of experimental procedures is provided. (B) Pretreatment of BDNF-shRNA, but not control-shRNA, notably abrogated the reversal effects of 0.3 mg/kg pemafibrate against CRS-induced depressive-like behaviors in the FST, TST, and SPT. A schematic timeline of experimental procedures is provided. All data are presented as means ± SEM (n = 10); ^**P < .01. n.s., no significance. The comparisons were made by 1-way ANOVA followed by Tukey test.

In summary, combined with the above pharmacological results involving GW6471 and K252a, it can be found that hippocampal PPARα and BDNF signaling are required for the antidepressant-like effects of pemafibrate in mice.

DISCUSSION

In the present study, we demonstrate that pemafibrate exerts antidepressant-like effects in mice comparable to fluoxetine, a widely used selective serotonin reuptake inhibitor. These effects are mediated, at least partially, through enhanced hippocampal PPARα and BDNF signaling pathways.

Pemafibrate is identified as a novel and highly selective modulator of PPARα.²⁴^,²⁵ Our rationale for investigating pemafibrate’s antidepressant properties stems from a comprehensive 2018 study on the role of central PPARα in depression.³⁰ To our knowledge, this study provides the first direct in vivo evidence supporting the antidepressant efficacy of pemafibrate. We employed 2 validated depression models: CUMS and CRS. Behavioral assessments included the FST, TST, and SPT. CUMS, the most widely recognized rodent depression model, effectively induces core depressive symptoms, including helplessness and anhedonia.⁴²^,⁴⁴ CRS has also been increasingly utilized in recent depression research.⁴³ While FST and TST evaluate behavioral despair, SPT measures anhedonia.^52–54 Fluoxetine (positive control) consistently reversed stress-induced behaviors across all tests, validating our experimental paradigm. There may be a limitation for this study, as we have used only male C57BL/6 J mice, while female subjects were not included due to limited resources in our laboratory. In addition, there are some other acknowledged models of depression besides CUMS and CRS, such as the chronic social defeat stress model.⁵⁵ The conclusion of this study would be further confirmed if pemafibrate treatment also reverses chronic social defeat stress–induced depressive-like symptoms in rodents. These limitations or shortcomings will be solved in the future.

Regarding the molecular mechanism underlying the antidepressant-like effects of pemafibrate found in this study, we focused on PPARα and BDNF based on previous findings that 3 other PPARα agonists (WY14643, fenofibrate, and gemfibrozil) exert antidepressant-like effects in mice by enhancing hippocampal PPARα and BDNF signaling.^31–33 Consistent with this hypothesis, our results from PPARα/BDNF immunoblotting and pharmacological/genetic interventions (GW6471, K252a, PPARα-shRNA, and BDNF-shRNA) collectively demonstrate that these 2 molecules mediate the antidepressant effects of pemafibrate. Our study provides the first evidence, to our knowledge, that pemafibrate enhances hippocampal BDNF expression and neurogenesis, which may facilitate future investigations into its pharmacological applications. Interestingly, while pemafibrate significantly increased hippocampal BDNF levels and neurogenesis under depressive-like conditions, this effect was not observed under normal conditions. The underlying mechanisms remain unclear but may involve differential regulation of negative feedback systems, analogous to the hypothalamic–pituitary–adrenal axis modulation.⁵⁶^,⁵⁷ Given BDNF and neurogenesis are implicated in various neurological disorders (e.g., Alzheimer disease, Parkinson disease, and stroke),^58–64 future studies should explore the therapeutic potential of pemafibrate in these conditions. Additionally, as BDNF in other brain regions (e.g., medial prefrontal cortex and nucleus accumbens) contributes to depression pathophysiology,^65–67 investigating their involvement in the effects of pemafibrate will be our next research focus.

Regarding the mechanism by which pemafibrate administration enhances hippocampal BDNF expression, existing evidence suggests that PPARα directly transcriptionally regulates CREB,⁶⁸ a downstream signaling molecule of BDNF that controls the biosynthesis of numerous proteins, including BDNF. Roy et al. in 2015 further demonstrated that simvastatin treatment upregulated the hippocampal BDNF expression in mice through PPARα-mediated transcriptional activation of CREB.⁶⁹ Therefore, the enhancing effects of pemafibrate on BDNF biosynthesis are likely mediated by PPARα activation. The neurobiology of depression is highly complex, involving multiple cellular systems. In addition to the monoaminergic and neurotrophic hypotheses, the neuroendocrine and neuroinflammation hypotheses propose that depression arises from hyperactivity of the hypothalamic–pituitary–adrenal axis and microglial dysfunction, respectively.⁷⁰^,⁷¹ Moreover, recent studies have identified an increasing number of proteins and signaling pathways implicated in depression, including mammalian target of rapamycin, vascular endothelial growth factor, histone deacetylase 5.^72–74 Although our pharmacological and genetic interventions (GW6471, K252a, PPARα-shRNA, and BDNF-shRNA) demonstrate that the antidepressant-like effects of pemafibrate require hippocampal PPARα and BDNF signaling, these findings do not exclude potential involvement of other molecular targets, which warrants further investigation. Nevertheless, our study provides novel insights into understanding the pharmacological effects of pemafibrate and may facilitate the development of more effective antidepressants with improved safety profiles.

Supplementary Material

Original_Western_Blotting_Images_pyaf063

original_western_blotting_images_pyaf063.docx^{(1.1MB, docx)}

Revised_Supplemental_Information_pyaf063

revised_supplemental_information_pyaf063.docx^{(50.8KB, docx)}

Acknowledgments

We sincerely thank Prof. Bo Jiang for kindly providing AAV-PPARα-shRNA-EGFP and AAV-BDNF-shRNA-EGFP.

Contributor Information

Jin Zhou, Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China.

Wei Zhao, Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China.

Hua Fan, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, Henan, China.

Si-Yi Zhou, Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China.

Xiao-Li Zhang, Department of Rheumatology and Immunology, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China.

Hui Xu, Department of Neurosurgery, Nantong Hospital of Traditional Chinese Medicine, Nantong 226009, Jiangsu, China.

Bo Jiang, Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China.

Wei Liu, Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China.

Zhi-Ming Cui, Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China.

Da-Wei Xu, Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong 226000, Jiangsu, China.

Author Contributions

Jin Zhou (Methodology [equal], Writing - original draft [equal]), Wei Zhao (Methodology [equal], Writing - original draft [equal]), Hua Fan (Methodology [supporting]), Si-Yi Zhou (Methodology [supporting]), Xiao-Li Zhang (Methodology [supporting]), Hui Xu (Methodology [supporting]), Bo Jiang (Conceptualization [supporting], Formal analysis [supporting], Investigation [supporting], Resources [supporting], Supervision [supporting], Visualization [supporting], Writing - review and editing [supporting]), Wei Liu (Methodology [supporting]), Zhi-Ming Cui (Conceptualization [supporting], Formal analysis [supporting], Funding acquisition [supporting], Investigation [supporting], Project administration [supporting], Resources [supporting], Supervision [supporting], Visualization [supporting], Writing - review and editing [supporting]), Da-wei Xu (Conceptualization [lead], Formal analysis [lead], Funding acquisition [lead], Investigation [lead], Project administration [lead], Resources [lead], Supervision [lead], Visualization [lead], Writing - review and editing [equal]).

Funding

This work was supported in part by grants from “333 Project” Scientific Research Project of Jiangsu Province (BRA2020204), Jiangsu Provincial Health Commission key project (K2024072), Research Project of Nantong Health Commission (MS2024025, MSZ2023026, MS2023041, and MS2023049), and Key Medical Talents Financial Assistance of Nantong (to Da-Wei Xu). They had no further role in the study design, collection and analysis of data, writing of the report, and paper submission.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability

The authors declare that all data supporting the findings of this study are available within the paper files.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Original_Western_Blotting_Images_pyaf063

original_western_blotting_images_pyaf063.docx^{(1.1MB, docx)}

Revised_Supplemental_Information_pyaf063

revised_supplemental_information_pyaf063.docx^{(50.8KB, docx)}

Data Availability Statement

The authors declare that all data supporting the findings of this study are available within the paper files.

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PERMALINK

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

Jin Zhou, MSc

Wei Zhao, MSc

Hua Fan, PhD

Si-Yi Zhou, MSc

Xiao-Li Zhang, MSc

Hui Xu, PhD

Bo Jiang, PhD

Wei Liu, PhD

Zhi-Ming Cui, PhD

Da-Wei Xu, PhD

Roles

Abstract

Background

Methods

Results

Conclusions

Highlights

INTRODUCTION

MATERIALS AND METHODS

Ethics Statements

Animals

Drugs

Forced Swim Test (FST)

Tail Suspension Test (TST)

Sucrose Preference Test (SPT)

Statistical Analysis

Additional Methods and Materials

RESULTS

Pemafibrate Treatment Significantly Reversed Both CUMS-Induced and CRS-Induced Depressive-like Behaviors in Mice

Figure 1.

Figure 2.

Pemafibrate Administration Notably Reversed Both CUMS-Induced and CRS-Induced Decrease in Hippocampal PPAR Expression, BDNF Signaling, and Neurogenesis in Mice

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Pharmacological Blockade of Hippocampal PPAR and BDNF Signaling Attenuated the Antidepressant-like Effects of Pemafibrate in Mice

Figure 7.

Genetic Knockdown of Hippocampal PPARα and BDNF Abolished the Antidepressant-like Effects of Pemafibrate in Mice

Figure 8.

Figure 9.

Figure 10.

DISCUSSION

Supplementary Material

Acknowledgments

Contributor Information

Author Contributions

Funding

Conflicts of Interest

Data Availability

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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