Increased brain uptake of γ-aminobutyric acid in a rabbit model of hepatic encephalopathy

Abstract

Transfer of the inhibitory neurotransmitter γ-aminobutyric acid across the normal blood-brain barrier is minimal. One prerequisite for γ-aminobutyric acid in plasma contributing to the neural inhibition of hepatic encephalopathy would be that increased transfer of γ-aminobutyric acid across the blood-brain barrier occurs in liver failure. The aim of the present study was to determine if brain γ-aminobutyric acid uptake is increased in rabbits with stage II–III (precoma) hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. A modification of the Oldendorf intracarotid artery-injection technique was applied. [3H] γ-aminobutyric acid, [14C] butanol, and 113mIn-labeled serum protein (transferrin) were injected simultaneously 4 s before decapitation. The ipsilateral brain uptake index of γ-aminobutyric acid was determined from measurements of the 3 isotopes in 5 brain regions. Uncorrected or simple brain uptake indices of [3H] γ-aminobutyric acid and [113mIn] transferrin were calculated using [14C] butanol as the highly extracted reference compound. The [113mIn] transferrin data were also used to “correct” the brain uptake index of [3H] γ-aminobutyric acid for intravascular retention of [3H] γ-aminobutyric acid. The methodology adopted minimized problems attributable to rapid [3H] γ-aminobutyric acid metabolism, and slow brain washout and recirculation of the radiolabeled tracers. Both the unconnected and corrected brain uptake indices of γ-aminobutyric acid as well as the simple brain uptake index of transferrin were significantly increased in both stage II and III hepatic encephalopathy in all brain regions studied. Moreover, these brain uptake indices were significantly greater in stage III hepatic encephalopathy than in stage II hepatic encephalopathy. These findings indicate that transfer of γ-aminobutyric acid from plasma to brain extracellular fluid is increased in the model of hepatic encephalopathy studied; hence, they provide support for the hypothesis that plasma-derived γ-aminobutyric acid may contribute to the neural inhibition of hepatic encephalopathy due to fulminant hepatic failure.