Amino Acid Release from Cerebral Cortex in Experimental Acute Liver Failure, Studied by In Vivo Cerebral Cortex Microdialysis

Abstract

Both increased gamma-aminobutyric acid (GABA)-ergic and decreased glutamatergic neurotransmission have been suggested relative to the pathophysiology of hepatic encephalopathy. This proposed disturbance in neurotransmitter balance, however, is based mainly on brain tissue analysis. Because the approach of whole tissue analysis is of limited value with regard to in vivo neurotransmission, we have studied the extracellular concentrations in the cerebral cortex of several neuroactive amino acids by application of the in vivo microdialysis technique. During acute hepatic encephalopathy induced in rats by complete liver ischemia, increased extracellular concentrations of the neuroactive amino acids glutamate, taurine, and glycine were observed, whereas extracellular concentrations of aspartate and GABA were unaltered and glutamine decreased. It is therefore suggested that hepatic encephalopathy is associated with glycine potentiated glutamate neurotoxicity rather than with a shortage of the neurotransmitter glutamate. In addition, increased extracellular concentration of taurine might contribute to the disturbed neurotransmitter balance. The observation of decreasing glutamine concentrations, after an initial increase, points to a possible astrocytic dysfunction involved in the pathophysiology of hepatic encephalopathy.

Glial uptake of neurotransmitter glutamate from the extracellular fluid studiedin vivoby microdialysis and13C NMR

“…6). The latter observation is in accord with a previous report that [GLU ECF ] was unchanged after a bolus NH 4 Ac injection into normal or portacaval shunted rats (Rao et al 1995), and its elevation occurs only after acute liver ischemia is induced by hepatic artery ligation in portacaval-shunted rats (Bosman et al 1992). Taken together, the results show that the glial GLU transporter was unimpaired by NH 4 Ac infusion under our experimental conditions.…”

The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy

“…The increase in extracellular concentrations of the above-mentioned amino acids in hyperammonaemia-induced encephalopathy is in agreement with other experimental studies who studied (sub)acute encephalopathy (40)(41)(42)(43). However, Rao et al (44) did not find similar increases.…”

Hypothermia in Acute Liver Failure

“…A consistent finding in experimental animal models of ALF is that of increased extracellular brain glutamate (Bosman et al, 1992;de Knegt et al, 1994;Hilgier et al, 1999;Michalak et al, 1996). This increased extracellular brain glutamate leads to increased glutamatergic neurotransmission which has been suggested to be implicated in the pathogenesis of CNS complications of ALF (Butterworth, 1997).…”