Acute acetaminophen intoxication induces direct neurotoxicity in rats manifested as astrogliosis and decreased dopaminergic markers in brain areas associated with locomotor regulation

Abstract

Acetaminophen (APAP) administration at therapeutic doses is safe, however overdosing produces hepatocellular injury via a multifactorial mechanism(s) that involves generation of reactive oxygen species (ROS), being the most common cause of acute liver failure (ALF) in the northern hemisphere. Brain alterations induced by APAP intoxication are usually considered secondary to hepatic encephalopathy development due to ALF. Although APAP is primarily metabolized in the liver, it is also distributed and metabolized homogeneously in the brain, affecting brain redox status. Nevertheless, comprehensive studies on the potential of APAP intoxication to produce brain toxicity are scarce. The aim of this study was to characterize the direct toxic effects of APAP in different regions of the brain and on behavior in rats where the magnitude of hepatotoxicity produced is not associated with ALF. The present work demonstrates that APAP intoxication producing hepatotoxicity, but not ALF in rats, is associated with marked hypolocomotion. Our studies also suggest that selective downregulation in dopamine levels in brain areas that regulate motor activity may be responsible, in part, for the decreased locomotion observed with APAP treatment. Furthermore, we observed that the brain histoarchitecture is conserved and that edema is not present. However, an increase in oxidative stress, reactive astrogliosis and a decrease in neuron processes are the main features observed in APAP-intoxicated animals. These effects might be partly due to direct toxic effects of APAP in brain, since the same reactive astrogliosis observed in rats was also observed in rat primary astrocyte cultures exposed to APAP.