Hepatic encephalopathy in cirrhotic and portacaval shunted dogs: Lack of changes in brain GABA uptake, brain GABA levels, brain glutamic acid decarboxylase activity and brain postsynaptic GABA receptors

Abstract

It has been suggested, from studies of a rabbit model of fulminant hepatic failure, that hepatic encephalopathy might be related to an increase in brain γ-aminobutyric acid uptake through a more permeable blood-brain barrier, leading to an overactivity of brain γ-aminobutyric acid-mediated inhibitory neurotrans-mission. Five groups of dogs were studied: normal dogs, dogs with secondary biliary cirrhosis without and with hepatic encephalopathy and portacaval shunted dogs without and with hepatic encephalopathy. Brain γ-aminobutyric acid and sucrose uptake was investigated using the multiple indicator dilution curve technique in unanesthetized dogs. Tracer doses of ^99mTc-labeled albumin (extracellular reference substance), ³H-labeled γ-aminobutyric acid and ¹⁴C-labeled sucrose prepared in autologous dog plasma were injected in one carotid artery, and dorsal sagittal sinus dilution curves were obtained. Uptake was calculated by comparing the areas under the ^99mTc-labeled albumin and the [³H]γ-aminobutyric acid (or [¹⁴C]sucrose) curves from appearance to peak height. After killing, brain γ-aminobutyric acid levels were measured in the frontal cortex by high-performance liquid chromatography and glutamic acid decarboxylase activities using a radioenzymatic assay. Brain γ-aminobutyric acid postsynaptic receptors were assessed using [³H]muscimol binding studies. There were no significant changes in cirrhotic and shunted dogs with or without hepatic encephalopathy with regard to brain γ-aminobutyric acid and sucrose uptake, brain γ-aminobutyric acid levels and glutamic acid decarboxylase activities. [³H]Muscimol binding studies did not show any changes in the number nor in the affinity of postsynaptic γ-aminobutyric acid receptors. Moreover, trypan blue injected in four dogs with hepatic encephalopathy did not induce a staining of the brain. These findings support neither a selective increase in brain γ-aminobutyric acid uptake in hepatic encephalopathy nor a physical breakdown of the blood-brain barrier. Moreover, brain studies suggest that impaired central γ-aminobutyric acid-ergic function does not play an important role in the pathogenesis of hepatic encephalopathy in dogs with cirrhosis or portacaval shunts.