CEREBRAL METABOLIC AND HISTOLOGICAL EFFECTS OF THIOACETAMIDE-INDUCED LIVER-FAILURE

Acute liver failure was induced in rats by successive administrations of thioacetamide over 3 days. At progressing stages of hepatic encepha lopathy (HE), brains were fixed with microwave irradiation for analysi s of metabolite levels or with formaldehyde for histopathological anal ysis. Metabolite levels were determined using H-1-nuclear magnetic res onance spectroscopy of perchloric acid extracts of the frontal cortex, parietial or occipital cortex, hippocampus, striatum, brain stem, and cerebellum. After thioacetamide treatment, thioacetamide and its meta bolites were detected in the brains at levels that did not correlate w ith the stage of HE. No changes were observed in the levels of N-acety laspartate, alanine, gamma-aminobutyric acid, aspartate, or inositol i n any brain region after thioacetamide treatment. HE was accompanied b y elevated glutamine, glucose, and lactate throughout the brain. At al l stages of HE, taurine was decreased in the neocortex and hippocampus , and glutamate and choline compounds were decreased in the frontal co rtex. None of the metabolite changes showed progression with the stage of HE. Progressing HE was accompanied by increasing neuronal injury i n layer III of the neocortex, in the Purkinje cells of the cerebellum, and in the hippocampus, particularly in the CA4 sector. The similarit y of this distribution of injury to that associated with excitotoxic i njury suggests that metabolic abnormalities after acute hepatic failur e may give rise to adverse effects at excitatory (glutamatergic) neuro nal receptors, leading to neuronal injury and clinical symptoms of pro gressing encephalopathy in this model. However, neuronal injury and th e presence of thioacetamide and its metabolites in the brain raise que stions about the validity of thioacetamide-induced liver failure as a model for clinical HE.