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Open Access Research article

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

Niels Steinebrunner14*, Carolin Mogler2, Spiros Vittas3, Birgit Hoyler1, Catharina Sandig1, Wolfgang Stremmel1 and Christoph Eisenbach1

Author Affiliations

1 Department of Gastroenterology, Hepatology, Intoxications and Infectious Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

2 Department of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany

3 Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

4 Mailing address: Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

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BMC Gastroenterology 2014, 14:148  doi:10.1186/1471-230X-14-148

Published: 19 August 2014

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.

Keywords:
Acute liver failure; Acetaminophen; Cholinergic anti-inflammatory pathway; Cholinesterase inhibition