In congenital urea cycle disorders, detoxification of ammonia is impaired, leading to hyperammonemia. Ammonia is the major component causing the acute neurological disturbances. It may influence the supply of substrate and its transport at the blood-brain barrier (BBB) which results in alterations in the synthesis and catabolism of neurotransmitters in the brain. In hyperammonemic rats, the uptake of tryptophan into the brain is increased with an augmented flux through the serotonin pathway. In the forebrain, glutamine as well as amino acids transported with the same L-carrier system, such as phenylalanine,tyrosine and tryptophan, are elevated. It is postulated that the increased transport of tryptophan at the BBB occurs in exchange with glutamine. Methionine sulfoximine (MSO) inhibits glutamine synthetase in the cerebral cortex. The activity drops from 5.85 ± 0.38 to 1.07 ±0.37 pmol/min/g wet weight. Under MSO, the brain tryptophan uptake also decreased to 64.2 ± 4.5% in hyperammonemic rats, to 54.1 ± 8.0% in untreated hyperammonemic rats,whereas without MSO an increase of tryptophan uptake was observed. An effect of glutamine on tryptophan transport could also be demonstrated using brain microvessel preparations as a model for the BBB. Our findings indicate that preloading isolated microvessels with Lglutamine increases tryptophan uptake into the endothelia when L-glutamine is at concentrations found in brain homogenates under hyperammonemia. Since brain microvessels do not contain glutamine synthetase activity, enzymes from the y-glutamyl cycle may be involved in the glutamine-mediated tryptophan transport. Using enzyme inhibitors (buthionine sulfoximine and AT-125), it could be shown that y-glutamyl cysteine synthetase as well as y-glutamyl transferase are involved in the glutamine-stimulated tryptophan uptake. From these experiments we draw the conclusion that not only ammonia but probably also glutamine plays an important role as a mediator of neurotransmitter precursor transport at the BBB.

Keywords:
Urea cycle, Tryptophan, Hyperammonemia, Neurotransmitter
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1987
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