Key role of PPAR-γ-mediated suppression of the NFκB signaling pathway in rutin's antidepressant effect

Shu-Yuan Yin; Xin-Xin Shao; Shi-Yu Shen; Jia-Rui Zhang; Zu-Qi Shen; Ling-Feng Liang; Cong Chen; Na Yue; Xian-Jun Fu; Jin Yu

doi:10.1016/j.phymed.2024.156178

Key role of PPAR-γ-mediated suppression of the NFκB signaling pathway in rutin's antidepressant effect

Phytomedicine. 2024 Oct 23:135:156178. doi: 10.1016/j.phymed.2024.156178. Online ahead of print.

Authors

Shu-Yuan Yin¹, Xin-Xin Shao², Shi-Yu Shen¹, Jia-Rui Zhang¹, Zu-Qi Shen¹, Ling-Feng Liang¹, Cong Chen², Na Yue³, Xian-Jun Fu⁴, Jin Yu⁵

Affiliations

¹ Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
² Institute for Traditional Chinese Medicine Literature and Culture, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
³ Department of Clinical Lab, Institute of Pediatrics of Weifang Medical University, Weifang Maternal and Child Health Hospital, Brunch of Shandong Provincial Clinical Research Center for Children's Health and Disease, Peking University Health Science Center-Weifang Joint Research Center for Maternal and Child Health, Weifang, 261061, China. Electronic address: 12111010098@alu.fudan.edu.cn.
⁴ Institute for Traditional Chinese Medicine Literature and Culture, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China. Electronic address: fuxianjun@sdutcm.edu.cn.
⁵ Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai 200433, China. Electronic address: yujin@shmu.edu.cn.

PMID: 39467428
DOI: 10.1016/j.phymed.2024.156178

Abstract

Background: Depression is a chronic and recurrent disorder with an unknown etiology. Efficacious antidepressant treatments with minimal side effects are urgently needed. Neuroinflammation may contribute to depression, as anti-inflammatory drugs have been shown to alleviate depressive symptoms in clinical practice. Rutin, a naturally occurring flavonoid derived from plants, is abundant in many antidepressant herbs, including Hemerocallis citrina Baroni. Historical Chinese medical texts, including the renowned Compendium of Materia Medica, document H. citrina Baroni as possessing antidepressant properties. Rutin, one of its primary active constituents, is recognized for its anti-inflammatory effects. Despite this, little is known about its specific target and mechanism.

Methods: In the present study, molecular docking, and surface plasmon resonance imaging (SPRi) analysis were used to identify the special targets of rutin. Meanwhile, the potential antidepressant effects were evaluated in the chronic social defeat stress (CSDS) paradigm, an animal model of depression. Then, Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), Co-immunoprecipitation (Co-IP) as well as antagonists of PPAR-γ were utilized to investigate the mechanism underlying the antidepressant effect of rutin.

Results: Both molecular docking and SPRi analysis showed high docking scores and interactions between rutin and PPAR-γ. In vivo, rutin promoted the nuclear translocation of PPAR-γ in the hippocampus of mice, inhibited NFκB-mediated inflammatory pathways, and subsequently reduced the expression of pro-inflammatory factors (e.g., iNOS, IL-6), aligning with an antidepressant effect. However, this therapeutic effect was attenuated by GW9662, a specific antagonist of PPAR-γ.

Conclusion: As a result of activating PPAR-γ and inhibiting NFκB pathway activation, rutin reduces neuroinflammation and exhibits an antidepressant effect. These findings shed light on the antidepressant mechanism of rutin and could be valuable for the development of new antidepressants.

Keywords: Antidepressant; NFκB signaling pathway; Neuroinflammation; PPAR-γ; Rutin.