Hepatic encephalopathy. Experimental studies in a rat model of fulminant hepatic failure.

Abstract

A new approach to pathogenetic study of hepatic encephalopathy was recently undertaken in order to identify the neurological alterations of the brain which characterize the coma. In this study attention was firstly addressed to a correct and objective evaluation of the comatose state in rats with fulminant hepatic failure induced by galactosamine. For this purpose visual evoked potentials were utilized since this electrophysiological test proved reliable and sensitive on the basis of an extensive pharmacological study. Two different stages of coma were identified in the rat and they were named mild and severe. Receptor binding studies performed on brain membranes of these rats show in the mild stage an increased number of low and high affinity GABA receptors and a decreased affinity of dopamine receptors. The severe stage is characterized by the persistence of only high affinity GABA receptors and a reduced number of dopamine receptors. This imbalance between inhibitory and excitatory receptor systems may explain the generalized central nervous system depression which characterizes the hepatic encephalopathy while the increased number of benzodiazepine receptors found in both stages of coma may account for the brain supersensitivity to sedative administration of patients with liver disease and for the sedative-induced episodes of coma. These receptor alterations may be attributed to a disuse and/or a partial degeneration of nerve terminals due to peripheral neurotoxins (i.e., ammonia, mercaptans, short chain fatty acids) and the decrease of glutamate decarboxylase activity and of zinc levels in brain tissues seems to be respectively a direct and an indirect demonstration of this phenomenon. Bearing in mind the supersensitivity of the GABA-benzodiazepine receptor system and their reciprocal interaction, a benzodiazepine antagonist was administered to rats in mild stage of encephalopathy. Electrophysiological and benzodiazepine binding studies demonstrated that this treatment can temporarily counteract some of the neurological disturbances of the earlier stage of coma and act as antidote of the sedative-induced episodes of coma.

• Authors: M L Zeneroli
• Journal: Journal of hepatology (J Hepatol) Vol. 1 Issue 3 Pg. 301-11 ( 1985) ISSN: 0168-8278 [Print] Netherlands
• PMID: 2999224 (Publication Type: Journal Article, Review)

Chemical References

• Receptors, Dopamine
• Receptors, GABA-A
• gamma-Aminobutyric Acid

Topics

• Animals
• Brain Chemistry
• Disease Models, Animal
• Evoked Potentials, Visual
• Hepatic Encephalopathy (etiology, metabolism, physiopathology)
• Rabbits
• Rats
• Receptors, Dopamine (analysis)
• Receptors, GABA-A (analysis)
• gamma-Aminobutyric Acid (metabolism)