N-Acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms
- 538 Downloads
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.
KeywordsAzoxymethane Acute liver failure N-acetylcysteine Hepatic encephalopathy Inflammation Brain edema Ammonia Glutathione
acute liver failure
tumor necrosis factor alpha
systemic inflammatory response syndrome
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.
- Gately MK, Warrier RR, Honasoge S, Carvajal DM, Faherty DA, Connaughton SE, Anderson TD, Sarmiento U, Hubbard BR, Murphy M (1994) Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocyte activity and induces production of IFN-gamma in vivo. Int Immunol 6:157–167CrossRefPubMedGoogle Scholar
- Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, Davern TJ 2nd, Murray NG, McCashland T, Reisch JS, Robuck PR, Acute Liver Failure Study Group (2009) Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 137:856–864Google Scholar
- Mumtaz K, Azam Z, Hamid S, Abid S, Memon S, Ali Shah H, Jafri W (2009) Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center without the facility of liver transplantation. Hepatol Int doi: 10.1007/s12072-009-9151-0