title: Pharmacologic cholinesterase inhibition improves survival in experimental sepsis.
abstract: OBJECTIVE
  Lethal sepsis occurs when an excessive inflammatory response evolves that cannot be controlled by physiologic anti-inflammatory mechanisms, such as the recently described cholinergic anti-inflammatory pathway. Here we studied whether the cholinergic anti-inflammatory pathway can be activated by pharmacologic cholinesterase inhibition in vivo.
  
  
  METHODS
  Prospective, randomized laboratory investigation that used an established murine sepsis model.
  
  
  METHODS
  Research laboratory in a university hospital.
  
  
  METHODS
  Female C57BL/6 mice.
  
  
  METHODS
  Sepsis in mice was induced by cecal ligation and puncture. Animals were treated immediately with intraperitoneal injections of nicotine (400 microg/kg), physostigmine (80 microg/kg), neostigmine (80 microg/kg), or solvent three times daily for 3 days.
  
  
  RESULTS
  Treatment with physostigmine significantly reduced lethality (p < or = .01) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine (p < or = .05). Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-kappaB (p < or = .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 (p < or = .001), and pulmonary neutrophil invasion (p < or = .05). Animals treated with the peripheral cholinesterase inhibitor neostigmine showed no difference compared with physostigmine-treated animals.
  
  
  CONCLUSIONS
  Our results demonstrate that cholinesterase inhibitors can be used successfully in the treatment of sepsis in a murine model and may be of interest for clinical use.
authors: Department of Anaesthesiology, University of Heidelberg, Heidelberg, Germany.
authors: Stefan
authors: S
authors: Hofer
authors: Christoph
authors: C
authors: Eisenbach
authors: Ivan K
authors: IK
authors: Lukic
authors: Lutz
authors: L
authors: Schneider
authors: Konrad
authors: K
authors: Bode
authors: Martina
authors: M
authors: Brueckmann
authors: Sven
authors: S
authors: Mautner
authors: Moritz N
authors: MN
authors: Wente
authors: Jens
authors: J
authors: Encke
authors: Jens
authors: J
authors: Werner
authors: Alexander H
authors: AH
authors: Dalpke
authors: Wolfgang
authors: W
authors: Stremmel
authors: Peter P
authors: PP
authors: Nawroth
authors: Eike
authors: E
authors: Martin
authors: Peter H
authors: PH
authors: Krammer
authors: Angelika
authors: A
authors: Bierhaus
authors: Markus A
authors: MA
authors: Weigand
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009388:Neostigmine / Q000627:therapeutic use*; D009538:Nicotine / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D010830:Physostigmine / Q000627:therapeutic use*; D018805:Sepsis / Q000097:blood / Q000188:drug therapy*
chemical_list: D002800:Cholinesterase Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D018722:Nicotinic Agonists; D009388:Neostigmine; D009538:Nicotine; D010830:Physostigmine