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Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse

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 cy...

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Autores principales: Steinebrunner, Niels, Mogler, Carolin, Vittas, Spiros, Hoyler, Birgit, Sandig, Catharina, Stremmel, Wolfgang, Eisenbach, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236504/
https://www.ncbi.nlm.nih.gov/pubmed/25139304
http://dx.doi.org/10.1186/1471-230X-14-148
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author Steinebrunner, Niels
Mogler, Carolin
Vittas, Spiros
Hoyler, Birgit
Sandig, Catharina
Stremmel, Wolfgang
Eisenbach, Christoph
author_facet Steinebrunner, Niels
Mogler, Carolin
Vittas, Spiros
Hoyler, Birgit
Sandig, Catharina
Stremmel, Wolfgang
Eisenbach, Christoph
author_sort Steinebrunner, Niels
collection PubMed
description 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.
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spelling pubmed-42365042014-11-19 Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse Steinebrunner, Niels Mogler, Carolin Vittas, Spiros Hoyler, Birgit Sandig, Catharina Stremmel, Wolfgang Eisenbach, Christoph BMC Gastroenterol Research Article 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. BioMed Central 2014-08-19 /pmc/articles/PMC4236504/ /pubmed/25139304 http://dx.doi.org/10.1186/1471-230X-14-148 Text en Copyright © 2014 Steinebrunner et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Steinebrunner, Niels
Mogler, Carolin
Vittas, Spiros
Hoyler, Birgit
Sandig, Catharina
Stremmel, Wolfgang
Eisenbach, Christoph
Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse
title Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse
title_full Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse
title_fullStr Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse
title_full_unstemmed Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse
title_short Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse
title_sort pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236504/
https://www.ncbi.nlm.nih.gov/pubmed/25139304
http://dx.doi.org/10.1186/1471-230X-14-148
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