Urea Cycle Disorders, Hyperammonemia and Neurotransmitter Changes

Abstract

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.

Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia

“…Chronic moderate hyperammonemia, similar to that present in cirrhotic patients, is enough to induce neuroinflammation and neurological alterations in rats without liver failure [ 4 , 8 ]. Although liver failure is the main cause of hyperammonemia, it also occurs in many other pathological situations, including congenital defects in enzymes of the urea cycle [ 9 ], in children with perinatal asphyxia or preterm delivery [ 10 , 11 ], Reye’s syndrome [ 12 ], hyperinsulinism-hyperammonemia syndrome [ 13 ], organic acidemias, and carnitine deficiencies [ 14 ]. Hyperammonemia may also arise as complications of valproate therapy, hemodialysis, or leukemia treatment [ 15 , 16 ].…”

“…As the anti-inflammatory treatments with ibuprofen or inhibitors of p38 mentioned above also restore the function of the pathway and learning ability [ 9 , 20 ], this suggests that neuroinflammation may be enhancing extracellular GABA in cerebellum which would mediate the impairing effects of neuroinflammation on the glutamate-NO-cGMP pathway and learning. A second aim of this study was to assess whether reduction of neuroinflammation in hyperammonemic rats by SFN normalizes in cerebellum in vivo the glutamate-NO-cGMP pathway and extracellular GABA concentration and analyze possible underlying mechanisms.…”

Benzoate stimulates glutamate release from perfused rat liver

“…Overdosage of benzoate produced symptoms similar to those found in hyperammonaemia (Batshaw et al, 1982). These symptoms may partly be attributed to neurotransmitter changes in the brain (Colombo, 1987). On the other hand, the deleterious effect of benzoate was attributed to the accumulation of benzoyl-CoA, which could deplete the acetyl-CoA pool, leading to an impaired formation of N-acetylglutamate and consequently an inhibition of urea synthesis (O'Connor et al, 1987;Wendler & Tremblay, 1982).…”

Intralysosomal Generation of Ammonia from Urea by Endocytosed Urease Results in Secretion of Free Lysosomal Arylsulfatase-A and Increased Activity of Membrane-Bound β-Glucosidase in Cultured Brain Cells

“…Ammonia is toxic to the nervous system and is a major contribut ing factor to the pathogenesis of hepatic en neurotoxic effects of even moderately severe hyperammonemia are particularly impor tant. Among the mechanisms proposed, whereby hyperammonemia could cause brain damage, interference with cellular en ergy metabolism or with the synthesis of neurotransmitters in neuronal cells, as well as with the transport of certain amino acids at the blood-brain barrier may be the most important ones [1,2], Another mechanism which may also take place in the brain is lysosomal dysfunction due to intralysosomal ammonium accumulation as described for other tissues [3,4], Toxicity of ammonia has been studied in primary cultures of astrocytes as an example of brain cells, expressing many of the charac teristics of their in vivo counterparts [5,6], Such systems are also increasingly used be cause of the legal restriction of in vivo ani mal experiments. The ammonia molecule is very volatile, water and fat soluble, so it dif fuses freely across lipid membranes through out all body fluid compartments [7], At an extracellular pH of 7.4, ammonia mostly ex ists in its protonated form as ammonium ions (NH4).…”