Dexmedetomidine inhibits inducible nitric oxide synthase in lipopolysaccharide-stimulated microglia by suppression of extracellular signal-regulated kinase

• Published in: Neurological research (New York) Vol. 37; no. 3; p. 238
• Main Authors: Zhang, Xiaobao, Wang, Jun, Qian, Wenyi, Zhao, Jingjing, Sun, Li, Qian, Yanning, Xiao, Hang
• Format: Journal Article
• Language: English
• Published: England 01.03.2015
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Blotting, Western; Cell Line; Dexmedetomidine - pharmacology; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases - metabolism; Flavonoids - pharmacology; JNK Mitogen-Activated Protein Kinases - metabolism; Lipopolysaccharides - toxicity; MAP Kinase Signaling System - drug effects; Mice; Microglia - drug effects; Microglia - enzymology; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - antagonists & inhibitors; Protein Kinase Inhibitors - pharmacology; Rats; Lipopolysaccharide; Signal transduction; Nitric oxide; Dexmedetomidine; Microglia
• ISSN: 1743-1328
• DOI: 10.1179/1743132814Y.0000000426

Dexmedetomidine (DEX) has been implicated in modulating the inflammatory response in central nervous system (CNS). However, the mechanism is still poorly understood. In this study, we evaluate the effects of DEX on lipopolysaccharide (LPS)-induced microglia activation and elucidate its possible signaling pathway involved in its anti-inflammatory effects. BV2 and primary microglia were pretreated with various concentrations of DEX (0·01, 0·1, 1, and 10 μM) and/or PD98059 for 1 hour, then microglia were incubated with LPS (1 μg/ml) for 24 hours. Nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression were measured by Griess reagent and real-time polymerase chain reaction. Furthermore, two intracellular signaling cascades including extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) were investigated by western blot analysis. Dexmedetomidine significantly attenuated LPS-induced NO production and iNOS expression in both BV2 cells and primary microglial cells. Lipopolysaccharide activated both ERK1/2 and JNK signal pathways; however, DEX exerted a specific inhibitory effect on ERK1/2 rather than JNK. Intriguingly, treatment of primary microglia and BV2 cells with DEX in combination with ERK1/2 inhibitor (PD98059) enhanced attenuation of LPS-induced NO production and iNOS expression. Dexmedetomidine attenuates NO and iNOS accumulation by inhibiting extracellular signal-regulated kinase (ERK) activation in both BV2 cells and primary microglial cells.