thioacetamide and ammonium-acetate

The phosphate-dependent (PAG) and phosphate-independent (PIndG) glutaminase activities were measured in cerebral perikaryal mitochondria derived from rats subjected to ammonium acetate- induced "simple" hyperammonemia (SHA) or thioacetamide-induced hepatic encephalopathy (HE). These two moderately hyperammonemic conditions were previously found to be accompanied by pronounced changes in virtually all the enzyme activities coupling the tricarboxylic acid cycle to the synthesis and metabolism of the excitatory neurotransmitter glutamate. Both PAG and PIndG remained unaffected by SHA or HE, indicating that they do not contribute to the cerebral glutamine/glutamate imbalance associated with both conditions.

Topics: Acetates; Animals; Brain; Citric Acid Cycle; Glutaminase; Hepatic Encephalopathy; Male; Mitochondria; Phosphates; Rats; Rats, Wistar; Thioacetamide

We investigated the role of brain peripheral-type benzodiazepine receptors (PBRs) and pregnenolone (a product of PBRs activation) in hepatic encephalopathy (HE)/hyperammonemia. Administration of the hepatotoxin, thioacetamide, or ammonium acetate to mice for 3 days significantly increased the number of brain PBRs (138-146% of control) and the affinity of the ligands for these receptors (2-fold). The total content of pregnenolone and its rate of synthesis in brain of the experimental animals were significantly increased. Our results suggest a novel integrated mechanism by which ammonia-induced activation of PBRs leads to elevated levels of pregnenolone-derived neurosteroids which are known to enhance GABA-ergic neurotransmission. This mechanism may play a pivotal role in pathogenesis of HE.

Topics: Acetates; Ammonia; Animals; Brain; Disease Models, Animal; Hepatic Encephalopathy; Liver Failure, Acute; Male; Mice; Neurons; Pregnenolone; Receptors, GABA-A; Thioacetamide

We measured the brain uptake index (BUI) for radiolabelled L-ornithine (ORN) in rats with acute hepatic encephalopathy (HE) induced by two (onset stage) or three (comatous stage) administrations of a hepatotoxin-thioacetamide (TAA). In the comatose group, an increase of the BUI to 275% of control was measured at 24 h post-treatment. In the onset group, the BUI for ORN increased gradually with time: it reached 220% of control at 7 days post-treatment and 442% of control at 21 days post-treatment. HE did not raise the BUI for a blood-brain barrier (BBB) non-penetrable amino acid L-aspartate (ASP), indicating that HE activates ORN transport but does not produce BBB leakage. ORN transport through BBB was not increased in rats with hyperammonemia comparable to that accompanying HE, but was induced without liver damage. Considering recent evidence that ORN acting intracerebrally ameliorates pathophysiological symptoms of HE, increased transport ORN across BBB should facilitate HE therapy based on systemic administration of this amino acid.

Topics: Acetates; Animals; Aspartic Acid; Blood-Brain Barrier; Brain; Endothelium; Hepatic Encephalopathy; Male; Models, Biological; Ornithine; Rats; Rats, Wistar; Thioacetamide

Brain edema in hepatic encephalopathy has been associated with circulating ammonia that is metabolized to glutamine. We measured alterations in blood chemistry and brain regional specific gravity and ion and amino acid contents in models of simple hyperammonemia and liver failure induced by daily administrations of ammonium acetate (AAc) or thioacetamide (TAA), respectively. Serum and brain ammonia increased to similar levels (200 and 170% of control, respectively) in both experimental groups. Serum transaminase activities increased 10-fold in animals injected with TAA but were unchanged in animals given AAc injections. In both experimental groups glutamine was elevated in cerebral white matter, cerebral gray matter, and basal ganglia, whereas brain tissue specific gravity decreased in all brain regions, indicating edema formation. In the AAc group, we observed a decrease in glutamate and taurine contents concomitant with the development of brain edema. In these animals, cerebral gray matter specific gravity and taurine contents returned to control levels 24 h after the third AAc injection. TAA-injected animals demonstrated similar decreases in brain tissue specific gravity, whereas glutamine, glutamate, and taurine contents were all elevated. During hepatic encephalopathy, ammonia-induced changes in brain amino acid content may contribute to brain edema development.

Topics: Acetates; Alanine Transaminase; Amino Acids; Ammonia; Animals; Aspartate Aminotransferases; Blood Proteins; Brain; Brain Edema; Hepatic Encephalopathy; Male; Potassium; Rats; Rats, Sprague-Dawley; Sodium; Thioacetamide

The calcium-dependent, high (65 mM) potassium-evoked release of the L-glutamate analogue [3H]D-aspartate (D-Asp) was measured in hippocampal slices derived from rats with (a) hepatic encephalopathy (HE) induced with a hepatotoxin, thioacetamide, (b) hyperammonemia produced by i.p. administration of ammonium acetate, and (c) in normal slices preincubated for 30 min with 1 mM ammonium acetate. HE (variant a) inhibited the release by about 30%, which was interpreted to indicate depressed exocytosis of synaptic glutamate. This phenomenon is likely to lead to a decrease of glutamate-mediated neural excitation, which in turn could contribute to the neural inhibition typical of HE. By contrast, and in agreement with earlier reports, hyperammonemia (variant b) did not affect D-Asp release, whereas in vitro treatment of the slices with ammonium acetate (variant c) resulted in a 60% increase of the release. Hence, impairment of synaptic glutamate exocytosis is the phenomenon that distinguishes HE related to toxic liver failure from simple hyperammonemia. This result emphasizes the role of other factors than ammonia in the pathophysiological mechanism of HE.

Topics: Acetates; Animals; Aspartic Acid; Female; Hepatic Encephalopathy; Hippocampus; In Vitro Techniques; Kinetics; Potassium; Radioisotope Dilution Technique; Rats; Rats, Inbred Strains; Thioacetamide; Tritium