Sevoflurane Exerts an Anti-depressive Action by Blocking the HMGB1/TLR4 Pathway in Unpredictable Chronic Mild Stress Rats
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This study was performed to investigate whether sevoflurane has an anti-depressive effect and to elucidate its underlying mechanism. Unpredictable chronic mild stress (uCMS)–treated rats were used for inducing depressive-like behavior and subsequently treated with sevoflurane. A forced swimming test was conducted with the rats. An ELISA was performed to detect the levels of brain-derived neurotrophic factor (BDNF) and inflammatory cytokines in the hippocampus of the rats. Differentially expressed genes in uCMS and normal rats were analyzed by microarray. qRT-PCR, western blot, and flow cytometry, and gain and loss of function measurements were carried out to determine the association between sevoflurane and the HMGB1/TLR4 pathway. A forced swimming test with uCMS rats exposed to sevoflurane demonstrated that a 2% sevoflurane treatment resulted in an anti-depressive effect. In addition, ELISAs of TNF-α (tumor necrosis factor-α), IL-1β (interleukin-1 beta), IL-6 (interleukin-6), and BDNF supported an effect of sevoflurane on inflammatory cytokines and a neurotrophic factor. HMGB1 was dramatically induced in uCMS rats, and the HMGB1/TLR4 pathway was implicated in sevoflurane exposure. A 2% sevoflurane treatment resulted in a restoration of HMGB1/TLR4 signaling and expression of cytokines and BDNF. HMGB1 overexpression partially prevented the protective effect of 2% SF, suggesting sevoflurane protects uCMS rats.
KeywordsDepression Sevoflurane HMGB1 TLR4
Zhenggang Guo and Feng Zhao contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Ye Wang (3rd), Ye Wang (4th), and Miaomiao Geng. Resources were collected by Yilei Zhang and Qingxia Ma. The first draft of the manuscript was written by Zhenggang Guo and Xiuzheng Xu. All authors commented on previous versions of the manuscript. Zhenggang Guo revised the manuscript critically. All authors read and approved the final manuscript.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of Peking University, Shougang Hospital. The animal experiments in this study followed the ARRIVE guidelines and were carried out in accordance with the U.K. Animals (Scientific Procedures) Act 1986 and associated guidelines and the EU Directive 2010/63/EU for animal experiments. This article does not contain any studies with human participants performed by any of the authors.
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