Sevoflurane Exerts an Anti-depressive Action by Blocking the HMGB1/TLR4 Pathway in Unpredictable Chronic Mild Stress Rats

Abstract

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.

Keywords: Depression; HMGB1; Sevoflurane; TLR4.