The pathogenesis of hepatic encephalopathy is largely unknown. Ammonia was the flrst toxin seriously considered to be of importance in the pathogenesis, has been subsequently rejected, but now appears to return to the forefront of "hepatic neurochemistry" (58). In theory, hyperammonemia can disturb normal brain ftmction through interference with basic cell metabolism (e.g. pH-regulation and water and energy balance)(59-61), electrophysiologic membrane ftmction (depending on ion pumps)(62) and biochemical communication between neurons, i.e. neurotransmission (depending on neurotransmitters). With regard to neurotransmission, one of the current opinions on the pathogenesis of hepatic encephalopathy is a dysbalance between neuro-inhibitory and neuro-excitatory neurotransmitters (63). Several groups have proposed that neuroinhibition via GABA or endogenous benzodiazepines is enhanced; we are investigating whether excitatory neurotransmission -especially glutamate neurotransmission- is altered during hepatic encephalopathy. The metabolism of glutamate, the most important excitatory neurotransmitter in the mammalian brain, is linked to that of ammonia (64,65). In neurons the neurotransmitter glutamate is produced from glutamine, through the enzymatic action of glutaminase. In vitro the activity of glutaminase, which is essential for the formation of glutamate, is inhibited by ammonia (66,67). Thus it was assumed that ammonia decreases the amount of glutamate in the brain, which probably would have an effect on normal brain function. Subsequently, the amount of glutamate was shown to be decreased in autopsied brain tissue from patients as well as animals with hepatic encephalopathy (22,68-70). However, these were whole brain studies in which the total amount of glutamate was assessed in all anatomical compartments together (vascular, intracellular and extracellular). The concentration of a neurotransmitter in the synaptic cleft, a part of the extracellular space, is probably the best reflection of neurotransmitter function. Since less than 1% of the total amount of antino acid in the brain is found in the extracellular space, total brain measurements are not suitable for determining neurotransmitter function (71). The brain dialysis technique has made the extracellular space more accessible for research (72-75). Furthermore, with brain dialysis one can distinguish between glutamate derived from basal cell metabolism and that attributable to neurogenic events (76,77). The aim of the present investigation was to determine in-vivo whether there is a hyperammonemia-induced deficit of the excitatory neurotransmitter glutamate in the extracellular space of the brain during encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. In our laboratory we have rabbit models for both acute ischemic liver failure and acute hyperammonemia (78,79). In the latter model ammonia is infused such that the plasma ammonia levels simulate those measured during acute ischemic liver failure (78). Because good animals models form a crucial part in experiments to unravel the mechanism of ammonia toxicity and its contribution to hepatic encephalopathy, this thesis also describes the clinical and biochemical details of our rabbit models for acute ischemic liver failure and acute hyperammonemia

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S.W. Schalm (Solko)
Erasmus University Rotterdam
Financial support for the publication of this thesis was kindly provided by Duphar Nederland B.V., Astra-Gastroenterologie, Glaxo-Gastroenterologie, Merck Sharp & Dohme and lnpharzam.
Erasmus MC: University Medical Center Rotterdam

de Knegt, R.J. (1993, June 16). Hepatic encephalopathy: experimental studies on the pathogenesis . Erasmus University Rotterdam. Retrieved from