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N-Acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms

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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 µg/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.

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Abbreviations

ALF:

acute liver failure

AOM:

azoxymethane

APAP:

acetaminophen

BBB:

blood-brain barrier

NAC:

N-acetylcysteine

IFN-γ:

interferon gamma

IL:

interleukin

TNF-α:

tumor necrosis factor alpha

SIRS:

systemic inflammatory response syndrome

ALT:

alanine aminotransferase

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Acknowledgments

This study was supported by a grant from the Canadian Institutes for Health Research. C.B. is a recipient of a fellowship from the Canadian Association for the Study of the Liver (CASL)/Astellas Pharma Canada. J.V. was supported by a fellowship from CASL/Schering Canada.

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Authors and Affiliations

  1. Neuroscience Research Unit, Hôpital Saint-Luc (CHUM), University of Montreal, 1058 St-Denis Street, Montreal, Quebec, H2X 3J4, Canada

    Chantal Bémeur, Javier Vaquero, Paul Desjardins & Roger F. Butterworth

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  1. Chantal Bémeur
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  2. Javier Vaquero
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  3. Paul Desjardins
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  4. Roger F. Butterworth
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Correspondence to Roger F. Butterworth.

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Bémeur, C., Vaquero, J., Desjardins, P. et al. N-Acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms. Metab Brain Dis 25, 241–249 (2010). https://doi.org/10.1007/s11011-010-9201-2

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  • DOI: https://doi.org/10.1007/s11011-010-9201-2

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