DNMT3a Downregulation Ttriggered Upregulation of GABAA Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice
Abstract Chemotherapeutic agents, such as paclitaxel (PTX), induce neuroplastic changes and alter gene expression in the prefrontal cortex (PFC), which may be associated with chemotherapy‐induced pain and negative emotions. Notably, DNA methylation undergoes adaptive changes in neurological disorder...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407387 |
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| author | Lixia Tian Xu‐Hui Li Yu‐Long Zhao Hui‐Yuan Yi Xue‐Ru Liu Rongrong Yao Xue‐Mei Hou Xuan Zhu Fu‐Quan Huo Tao Chen Lingli Liang |
| author_facet | Lixia Tian Xu‐Hui Li Yu‐Long Zhao Hui‐Yuan Yi Xue‐Ru Liu Rongrong Yao Xue‐Mei Hou Xuan Zhu Fu‐Quan Huo Tao Chen Lingli Liang |
| author_sort | Lixia Tian |
| collection | DOAJ |
| description | Abstract Chemotherapeutic agents, such as paclitaxel (PTX), induce neuroplastic changes and alter gene expression in the prefrontal cortex (PFC), which may be associated with chemotherapy‐induced pain and negative emotions. Notably, DNA methylation undergoes adaptive changes in neurological disorders, emerging as a promising target for neuromodulation. In this study, systemic administration of PTX leads to a decrease in the expression of the DNA methyltransferase DNMT3a, while concurrently upregulating the expression of Gabrb1 mRNA and its encoded GABAARβ1 protein in the medial PFC (mPFC) of male mice. Overexpression of DNMT3a in the mPFC alleviates PTX‐induced pain hypersensitivity, and anxiety‐like behavior in these mice. Additionally, it reverses the PTX‐induced increase in inhibitory synaptic transmission in the pyramidal neurons of the mPFC. Mechanistically, the upregulation of GABAARβ1 in the mPFC is linked to the reduced expression of DNMT3a and DNA hypomethylation at the promoter region of the Gabrb1 gene. Furthermore, a long‐term diet rich in methyl donors alleviates PTX‐induced pain hypersensitivity and anxiety‐like behavior in mice. These findings suggest that the DNMT3a‐mediated upregulation of GABAARβ1 in the mPFC contributes to PTX‐induced neuropathic pain and anxiety, highlighting DNA methylation‐dependent epigenetic regulation as a potential therapeutic target for addressing chemotherapy‐induced cortical dysfunction. |
| format | Article |
| id | doaj-art-20ec0a216aff4e35885bc0cee0406286 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-20ec0a216aff4e35885bc0cee04062862025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202407387DNMT3a Downregulation Ttriggered Upregulation of GABAA Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male MiceLixia Tian0Xu‐Hui Li1Yu‐Long Zhao2Hui‐Yuan Yi3Xue‐Ru Liu4Rongrong Yao5Xue‐Mei Hou6Xuan Zhu7Fu‐Quan Huo8Tao Chen9Lingli Liang10Department of Physiology and Pathophysiology School of Basic Medical Sciences Institute of Neuroscience Translational Medicine Institute Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 P. R. ChinaCenter for Neuron and Disease Frontier Institutes of Science and Technology Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences Institute of Neuroscience Translational Medicine Institute Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 P. R. ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences Institute of Neuroscience Translational Medicine Institute Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 P. R. ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences Institute of Neuroscience Translational Medicine Institute Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 P. R. ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences Institute of Neuroscience Translational Medicine Institute Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 P. R. ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences Institute of Neuroscience Translational Medicine Institute Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 P. R. ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences Institute of Neuroscience Translational Medicine Institute Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 P. R. ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences Institute of Neuroscience Translational Medicine Institute Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 P. R. ChinaDepartment of Anatomy and K.K. Leung Brain Research Centre Fourth Military Medical University Xi'an 710032 P. R. ChinaDepartment of Physiology and Pathophysiology School of Basic Medical Sciences Institute of Neuroscience Translational Medicine Institute Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 P. R. ChinaAbstract Chemotherapeutic agents, such as paclitaxel (PTX), induce neuroplastic changes and alter gene expression in the prefrontal cortex (PFC), which may be associated with chemotherapy‐induced pain and negative emotions. Notably, DNA methylation undergoes adaptive changes in neurological disorders, emerging as a promising target for neuromodulation. In this study, systemic administration of PTX leads to a decrease in the expression of the DNA methyltransferase DNMT3a, while concurrently upregulating the expression of Gabrb1 mRNA and its encoded GABAARβ1 protein in the medial PFC (mPFC) of male mice. Overexpression of DNMT3a in the mPFC alleviates PTX‐induced pain hypersensitivity, and anxiety‐like behavior in these mice. Additionally, it reverses the PTX‐induced increase in inhibitory synaptic transmission in the pyramidal neurons of the mPFC. Mechanistically, the upregulation of GABAARβ1 in the mPFC is linked to the reduced expression of DNMT3a and DNA hypomethylation at the promoter region of the Gabrb1 gene. Furthermore, a long‐term diet rich in methyl donors alleviates PTX‐induced pain hypersensitivity and anxiety‐like behavior in mice. These findings suggest that the DNMT3a‐mediated upregulation of GABAARβ1 in the mPFC contributes to PTX‐induced neuropathic pain and anxiety, highlighting DNA methylation‐dependent epigenetic regulation as a potential therapeutic target for addressing chemotherapy‐induced cortical dysfunction.https://doi.org/10.1002/advs.202407387anxietyDNMT3aGABAA receptorpaclitaxelneuropathic pain |
| spellingShingle | Lixia Tian Xu‐Hui Li Yu‐Long Zhao Hui‐Yuan Yi Xue‐Ru Liu Rongrong Yao Xue‐Mei Hou Xuan Zhu Fu‐Quan Huo Tao Chen Lingli Liang DNMT3a Downregulation Ttriggered Upregulation of GABAA Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice Advanced Science anxiety DNMT3a GABAA receptor paclitaxel neuropathic pain |
| title | DNMT3a Downregulation Ttriggered Upregulation of GABAA Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice |
| title_full | DNMT3a Downregulation Ttriggered Upregulation of GABAA Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice |
| title_fullStr | DNMT3a Downregulation Ttriggered Upregulation of GABAA Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice |
| title_full_unstemmed | DNMT3a Downregulation Ttriggered Upregulation of GABAA Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice |
| title_short | DNMT3a Downregulation Ttriggered Upregulation of GABAA Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice |
| title_sort | dnmt3a downregulation ttriggered upregulation of gabaa receptor in the mpfc promotes paclitaxel induced pain and anxiety in male mice |
| topic | anxiety DNMT3a GABAA receptor paclitaxel neuropathic pain |
| url | https://doi.org/10.1002/advs.202407387 |
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