Evidence for the role of ammonia in the intracerebral transfer and metabolism of tryptophan

Grippon, P.; Lafitte, Monique le Poncin; Boschat, M; Wang, Shwen; Faure, Grazyna; Dutertre, Dominique; Opolon, P

doi:10.1002/hep.1840060424

Cited by 33 publications

(10 citation statements)

References 25 publications

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“…[7]. This was also recently observed by Grippon et al [13], who showed that when tryptophan and ammonia were infused simultaneously into the carotid artery of the rat, tryptophan and 5-HIAA but not 5-HT increased in the hypo thalamus without changes in cerebral blood flow. Similar changes were described in orni thine carbamyltransferase (OCT)-deficient sparse-fur mice, a natural animal model for a urea cycle defect, also presenting with hyper ammonemia.…”

supporting

confidence: 64%

Urea Cycle Disorders, Hyperammonemia and Neurotransmitter Changes

Colombo

1987

Enzyme

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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.

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supporting

confidence: 64%

Urea Cycle Disorders, Hyperammonemia and Neurotransmitter Changes

Colombo

1987

Enzyme

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“…Our data suggest that increased circulating (32, 33) and brain (33)(34)(35)(36) glutamine levels leading to increased concentrations and release of brain GABA may be involved in the hepatic encephalopathy of liver failure and ammonia toxicity (37). GABAergic transmission has been implicated in the pathogenesis of hepatic encephalopathy (38,39), and antagonists of GABA receptors can ameliorate manifestations of this disorder.…”

Section: Discussionmentioning

confidence: 95%

Oral L‐glutamine increases GABA levels in striatal tissue and extracellular fluid

Wang¹,

Maher²,

Wurtman³

2007

FASEB j.

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We explored the possibility that circulating glutamine affects gamma-aminobutyric acid (GABA) levels in rat striatal tissue and GABA concentrations in striatal extracellular fluid (ECF). Striatal microdialysates, each collected over a 20 min interval, were obtained after no treatment, oral L-glutamine (0.5 g/kg), or glutamine followed by NMDA (administered via the microdialysis probe). GABA concentrations were measured by HPLC using a stable OPA/sulfite precolumn derivatization and an electrochemical detection method. L-Glutamine administration significantly increased ECF GABA concentrations by 30%, and enhanced the response evoked by NMDA alone (70%) to 120% over baseline (all P<0.05). Striatal GABA levels increased significantly 2.5 h after oral L-glutamine (e.g., from 1.76 +/- 0.04 micromol/g in vehicle-treated rats to 2.00 +/- 0.15 micromol/g in those receiving 2.0 g/kg of glutamine). Striatal glutamine levels also increased significantly, but not those of glutamate. These data suggest that GABA synthesis in, and release from, rat striatum may be regulated in part by circulating glutamine. Hence, glutamine administration may provide a useful adjunct for treating disorders (e.g., anxiety, seizures) when enhanced GABAergic transmission is desired. Moreover, the elevation in plasma and brain glutamine associated with hepatic failure may, by increasing brain GABA release, produce some of the manifestations of hepatic encephalopathy.

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“…In contrast, there may be causes of serotonergic terminal damage that are especially ammonia-dependent. Specifically, hyperammoniemia increases the uptake of L-tryptophan (Grippon et al, 1986), the expression and activity of monoamine oxidase (Mousseau et al, 1997), and production of 5-HIAA (Batshaw et al, 1986). Accordingly, ammonia-induced increases in 5-HT turnover may increase the production of oxidative intermediates.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Halpin

Yamamoto

2012

J. Neurosci.

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Ammonia is metabolized by the liver and has established neurological effects. The current study examined the possibility that ammonia contributes to the neurotoxic effects of methamphetamine (METH). The results show that a binge dosing regimen of METH to the rat increased plasma and brain ammonia concentrations that were paralleled by evidence of hepatotoxicity. The role of peripheral ammonia in the neurotoxic effects of METH was further substantiated by the demonstration that the enhancement of peripheral ammonia excretion blocked the increases in brain and plasma ammonia and attenuated the long term depletions of dopamine and serotonin typically produced by METH. Conversely, the localized perfusion of ammonia in combination with METH, but not METH alone or ammonia alone, into the striatum recapitulated the neuronal damage produced by the systemic administration of METH. Furthermore, this damage produced by the local administration of ammonia and METH was blocked by the GYKI 52466, an AMPA receptor antagonist. These findings highlight the importance of ammonia derived from the periphery as a small molecule mediator of METH neurotoxicity and more broadly emphasize the importance of peripheral organ damage as a possible mechanism that mediates the neuropathology produced by drugs of abuse and other neuroactive molecules.

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Evidence for the role of ammonia in the intracerebral transfer and metabolism of tryptophan

Cited by 33 publications

References 25 publications

Urea Cycle Disorders, Hyperammonemia and Neurotransmitter Changes

Urea Cycle Disorders, Hyperammonemia and Neurotransmitter Changes

Oral L‐glutamine increases GABA levels in striatal tissue and extracellular fluid

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

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