DNMT3a Downregulation Ttriggered Upregulation of GABA A Receptor in the mPFC Promotes Paclitaxel-Induced Pain and Anxiety in Male Mice.

Autor: Tian L; Department 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. China., Li XH; Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P. R. China., Zhao YL; Department 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. China., Yi HY; Department 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. China., Liu XR; Department 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. China., Yao R; Department 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. China., Hou XM; Department 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. China., Zhu X; Department 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. China., Huo FQ; Department 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. China., Chen T; Department of Anatomy and K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an, 710032, P. R. China., Liang L; Department 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. China.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Dec 16, pp. e2407387. Date of Electronic Publication: 2024 Dec 16.
DOI: 10.1002/advs.202407387
Abstrakt: 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 GABA A Rβ1 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 GABA A Rβ1 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 GABA A Rβ1 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.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
Externí odkaz: