title: Dexmedetomidine inhibits inducible nitric oxide synthase in lipopolysaccharide-stimulated microglia by suppression of extracellular signal-regulated kinase.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Dexmedetomidine attenuates NO and iNOS accumulation by inhibiting extracellular signal-regulated kinase (ERK) activation in both BV2 cells and primary microglial cells.
authors.forename: Xiaobao
authors.initials: X
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Wenyi
authors.initials: W
authors.lastname: Qian
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Yanning
authors.initials: Y
authors.lastname: Qian
authors.forename: Hang
authors.initials: H
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D020927:Dexmedetomidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005419:Flavonoids; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D020927:Dexmedetomidine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Dexmedetomidine,; Lipopolysaccharide,; Microglia,; Nitric oxide; Signal transduction,