title: Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse.
abstract: BACKGROUND
  Acetaminophen (APAP) is one of the most widely used analgesic and antipyretic pharmaceutical substances in the world and accounts for most cases of drug induced liver injury resulting in acute liver failure. Acute liver failure initiates a sterile inflammatory response with release of cytokines and innate immune cell infiltration in the liver. This study investigates, whether pharmacologic acetylcholinesterase inhibition with neostigmine diminishes liver damage in acute liver failure via the cholinergic anti-inflammatory pathway.
  
  
  METHODS
  Acute liver failure was induced in BALB/c mice by a toxic dose of acetaminophen (APAP). Neostigmine and/or N-acetyl-cysteine (NAC) were applied therapeutically at set time points and the survival was investigated. Liver damage was assessed by serum parameters, histopathology and serum cytokine assays 12 h after initiation of acute liver failure.
  
  
  RESULTS
  Serum parameters, histopathology and serum cytokine assays showed pronounced features of acute liver failure 12 h after application of acetaminophen (APAP). Neostigmine treatment led to significant reduction of serum liver enzymes (LDH (47,147 ± 12,726 IU/l vs. 15,822 ± 10,629 IU/l, p = 0.0014) and ALT (18,048 ± 4,287 IU/l vs. 7,585 ± 5,336 IU/l, p = 0.0013), APAP-alone-treated mice vs. APAP + neostigmine-treated mice), inflammatory cytokine levels (IL-1β (147 ± 19 vs. 110 ± 25, p = 0.0138) and TNF-α (184 ± 23 vs. 130 ± 33, p = 0.0086), APAP-alone-treated mice vs. APAP + neostigmine-treated mice) and histopathological signs of damage.Animals treated with NAC in combination with the peripheral cholinesterase inhibitor neostigmine showed prolonged survival and improved outcome.
  
  
  CONCLUSIONS
  Neostigmine is an acetylcholinesterase inhibitor that ameliorates the effects of APAP-induced acute liver failure in the mouse and therefore may provide new treatment options for affected patients.
authors.affiliation: Department of Gastroenterology, Hepatology, Intoxications and Infectious Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. niels.steinebrunner@med.uni-heidelberg.de.
authors.forename: Niels
authors.initials: N
authors.lastname: Steinebrunner
authors.forename: Carolin
authors.initials: C
authors.lastname: Mogler
authors.forename: Spiros
authors.initials: S
authors.lastname: Vittas
authors.forename: Birgit
authors.initials: B
authors.lastname: Hoyler
authors.forename: Catharina
authors.initials: C
authors.lastname: Sandig
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: Christoph
authors.initials: C
authors.lastname: Eisenbach
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology; D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology / Q000401:mortality*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D053583:Interleukin-1beta / Q000187:drug effects / Q000276:immunology; D045022:Lactate Dehydrogenases / Q000097:blood / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000276:immunology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000276:immunology / Q000401:mortality*; D051379:Mice; D008807:Mice, Inbred BALB C; D009388:Neostigmine / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology
chemical_list: D018712:Analgesics, Non-Narcotic; D002800:Cholinesterase Inhibitors; D016166:Free Radical Scavengers; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D009388:Neostigmine; D045022:Lactate Dehydrogenases; D000410:Alanine Transaminase; D000111:Acetylcysteine