Jin Zhou, Wei Zhao, Hua Fan, Si-Yi Zhou, Xiao-Li Zhang, Hui Xu, Bo Jiang, Wei Liu, Zhi-Ming Cui, Da-Wei Xu
{"title":"通过激活海马PPARa和BDNF信号通路,帕马替特治疗在CUMS和CRS模型中产生抗抑郁样作用。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Pemafibrate exerts antidepressant-like effects in both CUMS and CRS mouse models by promoting hippocampal PPARα and BDNF signaling.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12452276/pdf/","citationCount":"0","resultStr":"{\"title\":\"Pemafibrate treatment produces antidepressant-like effects in CUMS and CRS models through activation of hippocampal PPARα and BDNF signaling.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Pemafibrate exerts antidepressant-like effects in both CUMS and CRS mouse models by promoting hippocampal PPARα and BDNF signaling.</p>\",\"PeriodicalId\":14134,\"journal\":{\"name\":\"International Journal of Neuropsychopharmacology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12452276/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Neuropsychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/ijnp/pyaf063\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Neuropsychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ijnp/pyaf063","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Pemafibrate treatment produces antidepressant-like effects in CUMS and CRS models through activation of hippocampal PPARα and BDNF signaling.
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.
期刊介绍:
The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.