Hepatic encephalopathy in thioacetamide-induced acute liver failure in rats: characterization of an improved model and study of amino acid-ergic neurotransmission.
An imbalance of excitatory and inhibitory amino acid-ergic neurotransmission has been suggested to play a role in the pathogenesis of hepatic encephalopathy. For further evaluation of this hypothesis, several parameters of amino acid-ergic neurotransmission were studied in rats with acute liver failure induced by the administration of 300 mg per kg thioacetamide by gavage on two consecutive days. By appropriate supportive care, hypoglycemia, renal failure and hypothermia were avoided. Rats were monitored clinically and neurologically. Hepatic encephalopathy evolved in four distinct, easily recognizable stages. Light and electron microscopic examination of brains of rats with hepatic encephalopathy revealed only a slight swelling of nuclei of neurons and astrocytes without signs of neuronal degeneration or brain edema. In rats with hepatic encephalopathy, the concentrations of GABA, glutamate and taurine were decreased in the cerebral cortex, the hippocampus and the striatum, whereas those of aspartate and glycine were unchanged or increased. GABAA and benzodiazepine receptors were studied as parameters for the postsynaptic GABAA-benzodiazepine receptor complex, glutamic acid decarboxylase as parameter for presynaptic GABA-ergic neurons and stimulation of benzodiazepine binding by GABA as a parameter for a GABA-mediated postsynaptic event. None of these parameters was different in hepatic encephalopathy as compared to controls. Similarly, Ca++/Cl(-)-dependent and -independent glutamate receptors as parameters for glutamatergic neurons were unchanged in rats with hepatic encephalopathy. Thus, in rats with thioacetamide-induced liver failure and hepatic encephalopathy, changes of the concentrations of neurotransmitter amino acids occur in the brain. Other neurochemical parameters, however, failed to identify alterations of GABA-ergic or glutamatergic neurotransmission in hepatic encephalopathy.
Zimmermann
C
C
Department of Gastroenterology and Hepatology, University of Vienna, Austria.
Ferenci
P
P
Pifl
C
C
Yurdaydin
C
C
Ebner
J
J
Lassmann
H
H
Roth
E
E
Hörtnagl
H
H
D000081:Acetamides / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D005971:Glutamates / Q000502:physiology*; D006501:Hepatic Encephalopathy / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D018377:Neurotransmitter Agents / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000502:physiology; D013154:Spleen / Q000473:pathology; D013853:Thioacetamide / Q000633:toxicity*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000081:Acetamides; D005971:Glutamates; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D013853:Thioacetamide; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase