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Antioxidant and anti-inflammatory effects of mild hypothermia in the attenuation of liver injury due to azoxymethane toxicity in the mouse

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Abstract

Previous studies have demonstrated protective effects of mild hypothermia following acetaminophen (APAP)-induced acute liver failure (ALF). However, effects of this treatment in ALF due to other toxins have not yet been fully investigated. In the present study, the effects of mild hypothermia in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines were assessed 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 stages of encephalopathy in parallel with AOM mice maintained mildly hypothermic (35°C). AOM treatment led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels, and brain GSH/GSSG ratios as well as selective increases in expression of plasma proinflammatory cytokines. Mild hypothermia resulted in reduced hepatic damage, improvement in neurological function, normalization of glutathione levels, and selective attenuation in expression of circulating proinflammatory cytokines. These findings demonstrate that the beneficial effects of mild hypothermia in experimental AOM-induced ALF involve both antioxidant and anti-inflammatory mechanisms.

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Abbreviations

ALF:

Acute liver failure

AOM:

Azoxymethane

APAP:

Acetaminophen

BBB:

Blood-brain barrier

IFN-γ:

Interferon-gamma

IL:

Interleukin

SIRS:

Systemic inflammatory response syndrome

TNF-α:

Tumor necrosis factor-alpha

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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.

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Authors and Affiliations

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

    Chantal Bémeur, Paul Desjardins & Roger F. Butterworth

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

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Bémeur, C., Desjardins, P. & Butterworth, R.F. Antioxidant and anti-inflammatory effects of mild hypothermia in the attenuation of liver injury due to azoxymethane toxicity in the mouse. Metab Brain Dis 25, 23–29 (2010). https://doi.org/10.1007/s11011-010-9186-x

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  • DOI: https://doi.org/10.1007/s11011-010-9186-x

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