N-acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms.
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 microg/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.
Bémeur
Chantal
C
University of Montreal, Montreal, Quebec, Canada.
Vaquero
Javier
J
Desjardins
Paul
P
Butterworth
Roger F
RF
D000082:Acetaminophen / Q000494:pharmacology; D000111:Acetylcysteine / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001397:Azoxymethane / Q000633:toxicity; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D004195:Disease Models, Animal; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000627:therapeutic use*; D017114:Liver Failure, Acute / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology
D000975:Antioxidants; D002273:Carcinogens; D016207:Cytokines; D018836:Inflammation Mediators; D000082:Acetaminophen; D001397:Azoxymethane; D000111:Acetylcysteine