title: Suppressive effects of levobupivacaine on endotoxin-induced microglial activation.
abstract: BACKGROUND
  We sought to elucidate the effects of levobupivacaine on modulating endotoxin-induced upregulation of inflammatory mediators and activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways in activated microglia.
  
  
  METHODS
  Confluent murine microglia (BV-2) were treated with endotoxin (lipopolysaccharide, 50 ng/mL) or endotoxin plus levobupivacaine (5, 25, or 50 μM) and denoted as the LPS, LPS + L(5), LPS + L(25), and LPS + L(50) groups, respectively. Levobupivacaine was administered immediately after endotoxin. Control groups were run simultaneously.
  
  
  RESULTS
  The concentrations of inflammatory mediators, including macrophage inflammatory protein-2 (P = 0.023 and 0.016), tumor necrosis factor-α (P = 0.025 and 0.020), interleukin (IL)-1β (P = 0.018 and 0.014), IL-6 (P = 0.029 and 0.023), nitric oxide (P = 0.025 and 0.026), and prostaglandin E2 (P = 0.028 and 0.016) of the LPS + L(25) and LPS + L(50) groups were significantly lower than those of the LPS group. The concentrations of macrophage inflammatory protein-2 (P = 0.035), IL-1β (P = 0.024), nitric oxide (P = 0.031), and prostaglandin E2 (P = 0.036) but not tumor necrosis factor-α and interleukin-6 of the LPS + L(5) group were also significantly lower than those of the LPS group. These data revealed that effects of endotoxin on upregulating inflammatory mediators were inhibited by levobupivacaine. Moreover, effects of endotoxin on activating NF-κB, including inhibitor-κB degradation, NF-κB nuclear translocation, and NF-κB-DNA binding, were also inhibited by levobupivacaine. Similarly, effects of endotoxin on activating MAPKs, including extracellular signal-regulated kinase, c-jun N-terminal kinase, and p38 MAPK, were also significantly inhibited by levobupivacaine.
  
  
  CONCLUSIONS
  Levobupivacaine significantly inhibited endotoxin-induced upregulation of inflammatory mediators and activation of NF-κB and MAPKs signaling pathways in activated microglia.
authors.affiliation: Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ya-Hsien
authors.initials: YH
authors.lastname: Huang
authors.forename: Jiin-Cherng
authors.initials: JC
authors.lastname: Yen
authors.forename: Jie-Jen
authors.initials: JJ
authors.lastname: Lee
authors.forename: Jyh-Fei
authors.initials: JF
authors.lastname: Liao
authors.forename: Wen-Jinn
authors.initials: WJ
authors.lastname: Liaw
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Huang
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D054426:Chemokine CXCL2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D000077554:Levobupivacaine; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D054426:Chemokine CXCL2; D004731:Endotoxins; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000077554:Levobupivacaine; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone; D002045:Bupivacaine
keywords: Chemokine; Cytokine; LPS; MAPK; Microglia; NF-κB