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Metab Brain Dis (2010) 25:241249 DOI 10.1007/s11011-010-9201-2
ORIGINAL PAPER
N-Acetylcysteine attenuates cerebral complicationsof non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms
Chantal Bmeur & Javier Vaquero & Paul Desjardins &
Roger F. Butterworth
Received: 28 October 2009 /Accepted: 4 November 2009 /Published online: 30 April 2010 # Springer Science+Business Media, LLC 2010
Abstract N-acetylcysteine (NAC) is an effective antidote to treat acetaminophen (APAP)-induced acute liver failure (ALF). NAC is hepatoprotective and prevents the neurological complications of ALF, namely hepatic encephalopathy and brain edema. The protective effect of NAC and its mechanisms of action in ALF due to other toxins, however, are still controversial. In the present study, we investigated the effects of NAC in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100 g/g; i.p.) or saline and sacrificed at coma stage of encephalopathy in parallel with AOM mice administered NAC (1.2 g/kg; i.p.). AOM administration led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels and brain GSH/GSSG ratios as well as increased expression of plasma proinflammatory cytokines. NAC treatment of AOM mice led to reduced hepatic damage and improvement in neurological function, normalization of brain and hepatic glutathione levels as well as selective attenuation in expression of plasma proinflammatory cytokines. These findings demonstrate that the beneficial effects of NAC in experimental non-APAP-induced ALF involves both antioxidant and anti-inflammatory mechanisms.
C. Bmeur : J. Vaquero : P. Desjardins : R. F. Butterworth (*) Neuroscience Research Unit, Hpital Saint-Luc (CHUM), University of Montreal, 1058 St-Denis Street,
Montreal, Quebec H2X 3J4, Canada e-mail: [email protected]
Keywords Azoxymethane . Acute liver failure . N-acetylcysteine . Hepatic encephalopathy . Inflammation . Brain edema . Ammonia . Glutathione
Abbreviations
ALF acute liver failure
AOM azoxymethane
APAP acetaminophen
BBB blood-brain barrier
NAC N-acetylcysteine
IFN- interferon gamma
IL interleukin
TNF- tumor necrosis factor alpha
SIRS systemic inflammatory response syndrome ALT alanine aminotransferase
Introduction
Acute liver failure (ALF) resulting from viral infection or toxic liver injury is a life-threatening condition. Mortality rates are extremely high with death resulting predominantly from brain...