Cerebral metabolic and histological effects of thioacetamide-induced liver failure

Abstract

Acute liver failure was induced in rats by successive administrations of thioacetamide over 3 days. At progressing stages of hepatic encephalopathy (HE), brains were fixed with microwave irradiation for analysis of metabolite levels or with formaldehyde for histopathological analysis. Metabolite levels were determined using 1H-nuclear magnetic resonance spectroscopy of perchloric acid extracts of the frontal cortex, parietal or occipital cortex, hippocampus, striatum, brain stem, and cerebellum. After thioacetamide treatment, thioacetamide and its metabolites were detected in the brains at levels that did not correlate with the stage of HE. No changes were observed in the levels of N-acetylaspartate, alanine, gamma-aminobutyric acid, aspartate, or inositol in any brain region after thioacetamide treatment. HE was accompanied by elevated glutamine, glucose, and lactate throughout the brain. At all stages of HE, taurine was decreased in the neocortex and hippocampus, and glutamate and choline compounds were decreased in the frontal cortex. None of the metabolite changes showed progression with the stage of HE. Progressing HE was accompanied by increasing neuronal injury in layer III of the neocortex, in the Purkinje cells of the cerebellum, and in the hippocampus, particularly in the CA4 sector. The similarity of this distribution of injury to that associated with excitotoxic injury suggests that metabolic abnormalities after acute hepatic failure may give rise to adverse effects at excitatory (glutamatergic) neuronal receptors, leading to neuronal injury and clinical symptoms of progressing encephalopathy in this model. However, neuronal injury and the presence of thioacetamide and its metabolites in the brain raise questions about the validity of thioacetamide-induced liver failure as a model for clinical HE.

Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia

“…For example, arterial ammonia concentrations show a significant positive correlation with the encephalopathy in patients with ALF [8]. Furthermore, both human [28] and experimental ALF resulting from hepatectomy [11], hepatic devascularization [17], [20], [31] and [35] or toxic liver injury [26] are all associated with increased brain concentrations of glutamine, a finding which has been attributed to increased removal of ammonia by brain via the activity of glutamine synthetase, a predominantly astrocytic enzyme. It has been proposed that the intracellular accumulation of glutamine is a major cause of cell swelling leading to brain edema in ALF [3].…”

“…Increased brain glutamine in animal models [2], [12], [17], [20], [25], [26], [31] and [25] as well as autopsied brain tissue from patients [28] with ALF have long been suggested to be a major factor determining brain edema and encephalopathy in this condition. However, an accumulating body of evidence suggests that other factors such as hyperemia and/or increased brain lactate production are also involved [6], [7], [15], [16] and [35].…”

Animal models of fulminant hepatic failure: A critical evaluation

“…Many different hepatotoxins, such as carbon tetrachloride, 20,21 thioacetamide, 22,23 nitrosamines, 24 halogenated anesthetics, 25,26 and murine hepatitis, 27,28 have been described in the literature. This review discusses two of the more widely used hepatotoxins, galactosamine [29][30][31][32][33][34][35][36] and acetaminophen.…”

Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

“…Since the brain cannot synthesize urea, detoxification of ammonia relies almost entirely on glutamine synthetase localized in astrocytes [88]. An increase of brain glutamine is a major feature in hyperammonemia or ALF [87], [89], [90], [91], [92], [93] and [94], and inhibition of glutamine synthesis attenuates ammonia-induced brain edema [87] and [89]. The osmotic effects of glutamine may partly explain the selective astrocytic swelling in ALF.…”

“…Increased brain lactate is common in animal models [77], [93], [94] and [121], and peaks of lactate in brain microdialysate preceding surges of ICP have been described in patients with ALF [98]. Increased brain lactate correlated with worsening encephalopathy and intracranial hypertension in experimental models [92] and [121], and it was due to increased de novo synthesis from circulating glucose.…”