Antidepressant-like activity of Bezafibrate in mice models of depression: a behavioral and neurobiological characterization
BackgroundDepression represents a major global public health challenge, inflicting profound suffering on patients while imposing substantial socioeconomic burdens on families and healthcare systems. Although monoamine-based antidepressants remain first-line pharmacotherapy, accumulating clinical evi...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1595341/full |
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| author | Dawei Xu Jin Zhou Siyi Zhou Weizhen Wang Chengniu Wang Bo Jiang Wei Zhao |
| author_facet | Dawei Xu Jin Zhou Siyi Zhou Weizhen Wang Chengniu Wang Bo Jiang Wei Zhao |
| author_sort | Dawei Xu |
| collection | DOAJ |
| description | BackgroundDepression represents a major global public health challenge, inflicting profound suffering on patients while imposing substantial socioeconomic burdens on families and healthcare systems. Although monoamine-based antidepressants remain first-line pharmacotherapy, accumulating clinical evidence reveals several limitations of these medications, including delayed pharmacodynamics and low remission rates. Therefore, it is necessary to search for new drugs and develop effective strategies for depression treatment. Bezafibrate (BEZ), which can activate proliferator-activated receptor a (PPARα), exhibit various biological functions, such as improving mitochondrial function, reducing neuroinflammation, and improving cognitive function. This study is to explore whether BEZ has antidepressant-like effects and its potential mechanisms.MethodsThe antidepressant effects and potential mechanisms of BEZ were assessed by using forced swim test, tail suspension test, sucrose preference test, Western blot, gene interference, and immunofluorescence in the chronic unpredictable mild stress (CUMS) models of depression.ResultsResults showed that BEZ treatment significantly reversed depressive behavior in CUMS mice. The administration of BEZ obviously promoted the expression of PPAR, enhanced the BDNF signaling pathway, promoted hippocampal neurogenesis in CUMS mice. In addition, the pharmacologcial inhibitors GW6471 and K252a were obviously prevented the antidepressant effect of BEZ. Furthermore, gene knockdown of hippocampal PPARα or BDNF by using AAV-PPARα-shRNA-EGFP and AAV-BDNF-shRNA-EGFP, can remarkably inhibit the antidepressant effect of BEZ.ConclusionCollectively, the behavioral and neurobiological results demonstrate that BEZ exhibits antidepressant-like activity through PPARα/BDNF signaling pathway and may use as a potential antidepressant. |
| format | Article |
| id | doaj-art-079bed2efa5f41f4a0faca687ea6c604 |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-079bed2efa5f41f4a0faca687ea6c6042025-08-20T02:20:10ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-04-011610.3389/fphar.2025.15953411595341Antidepressant-like activity of Bezafibrate in mice models of depression: a behavioral and neurobiological characterizationDawei Xu0Jin Zhou1Siyi Zhou2Weizhen Wang3Chengniu Wang4Bo Jiang5Wei Zhao6Department of Orthopaedics, Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Orthopaedics, Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Orthopaedics, Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaInstitute of Reproductive Medicine, Medical College, Nantong University, Nantong, Jiangsu, ChinaInstitute of Reproductive Medicine, Medical College, Nantong University, Nantong, Jiangsu, ChinaDepartment of Pharmacology, Pharmacy College, Nantong University, Nantong, Jiangsu, ChinaDepartment of Neurosurgery, Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaBackgroundDepression represents a major global public health challenge, inflicting profound suffering on patients while imposing substantial socioeconomic burdens on families and healthcare systems. Although monoamine-based antidepressants remain first-line pharmacotherapy, accumulating clinical evidence reveals several limitations of these medications, including delayed pharmacodynamics and low remission rates. Therefore, it is necessary to search for new drugs and develop effective strategies for depression treatment. Bezafibrate (BEZ), which can activate proliferator-activated receptor a (PPARα), exhibit various biological functions, such as improving mitochondrial function, reducing neuroinflammation, and improving cognitive function. This study is to explore whether BEZ has antidepressant-like effects and its potential mechanisms.MethodsThe antidepressant effects and potential mechanisms of BEZ were assessed by using forced swim test, tail suspension test, sucrose preference test, Western blot, gene interference, and immunofluorescence in the chronic unpredictable mild stress (CUMS) models of depression.ResultsResults showed that BEZ treatment significantly reversed depressive behavior in CUMS mice. The administration of BEZ obviously promoted the expression of PPAR, enhanced the BDNF signaling pathway, promoted hippocampal neurogenesis in CUMS mice. In addition, the pharmacologcial inhibitors GW6471 and K252a were obviously prevented the antidepressant effect of BEZ. Furthermore, gene knockdown of hippocampal PPARα or BDNF by using AAV-PPARα-shRNA-EGFP and AAV-BDNF-shRNA-EGFP, can remarkably inhibit the antidepressant effect of BEZ.ConclusionCollectively, the behavioral and neurobiological results demonstrate that BEZ exhibits antidepressant-like activity through PPARα/BDNF signaling pathway and may use as a potential antidepressant.https://www.frontiersin.org/articles/10.3389/fphar.2025.1595341/fullBezafibratedepressionPPARαBNDFCUMS |
| spellingShingle | Dawei Xu Jin Zhou Siyi Zhou Weizhen Wang Chengniu Wang Bo Jiang Wei Zhao Antidepressant-like activity of Bezafibrate in mice models of depression: a behavioral and neurobiological characterization Frontiers in Pharmacology Bezafibrate depression PPARα BNDF CUMS |
| title | Antidepressant-like activity of Bezafibrate in mice models of depression: a behavioral and neurobiological characterization |
| title_full | Antidepressant-like activity of Bezafibrate in mice models of depression: a behavioral and neurobiological characterization |
| title_fullStr | Antidepressant-like activity of Bezafibrate in mice models of depression: a behavioral and neurobiological characterization |
| title_full_unstemmed | Antidepressant-like activity of Bezafibrate in mice models of depression: a behavioral and neurobiological characterization |
| title_short | Antidepressant-like activity of Bezafibrate in mice models of depression: a behavioral and neurobiological characterization |
| title_sort | antidepressant like activity of bezafibrate in mice models of depression a behavioral and neurobiological characterization |
| topic | Bezafibrate depression PPARα BNDF CUMS |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1595341/full |
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