• Fujun Wang, Yong Meng, Yiwei Zhang, Guoguang Zhao, Xiaonan Zheng, Qifeng Xiao, and Yang Yu.
• Department of Anaesthesiology, Affiliated Hospital of Taishan Medical College, Taian, Shandong, China.
• J. Surg. Res. 2015 Apr 1;194(2):599-613.

BackgroundKetamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, is widely used as an intravenous anesthetic agent and has also been shown to possess anti-inflammatory effects, but its effects on high-mobility group box-1 (HMGB1) have not been well defined. In the present study, we investigated the effects of ketamine on HMGB1 in lipopolysaccharide (LPS)-induced Raw264.7 cells and in a mouse model of cecal ligation and puncture-induced sepsis.Materials And MethodsRaw264.7 cells were incubated with or without 1 μg/mL LPS in the presence or absence of ketamine, mitogen-activated protein kinases (MAPKs) inhibitor, or small interfering RNA (siRNA). The protein and expression levels of inflammatory mediators, such as HMGB1, nitric oxide (NO), and heme oxygenase-1 (HO-1), were measured using enzyme-linked immunosorbent assays, Western blot analysis, and real-time polymerase chain reaction. The effect of ketamine on nuclear factor erythroid 2-related factor 2 (Nrf2) and MAPKs activation was evaluated using enzyme-linked immunosorbent assays and Western blot analysis.ResultsIn vitro, ketamine inhibits HMGB1 and NO release and induces HO-1 expression in a concentration-dependent manner, whereas HO-1 siRNA antagonizes the inhibition of HMGB1 and NO. The effect of ketamine is inhibited by the p38 MAPK inhibitor SB203580 and Nrf2 siRNA, indicating that ketamine induces HO-1 via p38 MAPK and Nrf2. In vivo, ketamine increases survival and decreases serum and lung HMGB1 levels in cecal ligation and puncture-induced sepsis.ConclusionsKetamine inhibits LPS-induced HMGB1 release through HO-1 induction, and these effects may be mediated by blockade of p38 MAPK and Nrf2 signaling pathways.Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

40 keywords...

hide…