Behavioral and Neurotransmitter Changes in the Urease-Infused Rat: A Model of Congenital Hyperammonemia

Batshaw, Mark L.; Hyman, Susan; Mellits, E. David; Thomas, George H.; DeMuro, Richard; Coyle, Joseph T.

doi:10.1203/00006450-198612000-00025

Cited by 39 publications

(16 citation statements)

References 15 publications

(20 reference statements)

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“…Plasma ammonium was measured by a microfluorometric adaptation of a glutamate dehydrogenase method as previously described (4). Whole blood and plasma (sodium heparin) were obtained by cardiac puncture under ether anesthesia using a 25-gauge needle.…”

Section: Methodsmentioning

confidence: 99%

“…Free and bound tryptophan were immediately separated by ultrafiltration (Amicon Centrifree ultrafilter) using fixed angle rotor centrifugation at room temperature for 20 min at 2000 X g. Total Trp concentrations in serum and free Trp in ultrafiltrates were measured immediately by an adaptation of an HPLC isocratic method with fluorometric detection as previously de-369 scribed (4,10). Using this approach, there was no difference in free Trp levels between paired samples measured with or without pH control.…”

Section: Methodsmentioning

confidence: 99%

“…Biogenic amines in cerebrospinal fluid and brain were determined by an isocratic HPLC method with electrochemical detection (4). Benzoate, phenylacetate, and hippurate concentrations were measured by an isocratic HPLC method with UV detection at 245 nm (1).…”

Section: Methodsmentioning

confidence: 99%

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Effect of Sodium Benzoate and Sodium Phenylacetate on Brain Serotonin Turnover in the Ornithine Transcarbamylase-Deficient Sparse-Fur Mouse

et al. 1988

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Herein we examine the effects of sodium benzoate and sodium phenylacetate on feeding and central serotonin turnover in a child with citrullinemia and in an animal model of congenital hyperammonemia, the ornithine transcarbamylase-deficient sparse-fur (spfly) mouse. In the child, when the benzoate/phenylacetate dosage was increased from 200 to 375 mg/kg/day each, feeding decreased. There was an accumulation of benzoate and phenylacetate in blood and cerebrospinal fluid a s well a s an increased concentration of 5-hydroxyindoleacetic acid, a neurochemical marker for serotonin turnover, in cerebrospinal fluid. In the mouse, sodium benzoate had a biphasic effect on both plasma ammonium levels and brain serotonin turnover. Two percent oral benzoate was associated with an increase in ammonium level, while a 3% dose led to a decrease in ammonium. There was a similar effect on serotonin turnover noted in both the hyperammonemic spfly and control CD-lly mice. Sodium phenylacetate did not have a consistent effect on serotonin turnover. The mechanism by which benzoate increases brain serotonin turnover appears to involve competition with tryptophan for albumin binding sites. This results in increased free tryptophan in serum and brain. W e speculate that some of the clinical symptoms of benzoate intoxication may be a consequence of altered serotonin turnover in the brain. We suggest that drug levels be monitored during therapy. 36excretion in children with inborn errors of urea synthesis (1). This has resulted in prolonged survival. However, both intravenous drugs used to treat acute hyperammonemia and inadvertent oral overdoses have been associated with clinical toxicity including anorexia, irritability, lethargy, and coma (1, 2). Symptoms of intoxication in part simulate those of hyperammonemia. The mechanism of these behavioral alterations is unclear. Bachmann et al. (3) re~orted increased brain uvtake of Tm. the precursor of serotbnin,tn rats injected with 1 mmol/kg of sddium benzoate. Increased brain uvtake of T m and increased brain serotonin turnover have also been reported in experimentally induced and naturally occurring hyperammonemia (4-7). These findings, together with data showing an association of anorexia with increased serotonin turnover in children with urea cycle disorders (8), suggest that benzoate intoxication may involve altered serotonin turnover.In studying the effect of benzoate and phenylacetate on serotonin turnover, we initially present a case report of a child with citrullinemia who developed toxic symptoms during high dose therapy and was found to have increased levels of the metabolite of serotonin, HIAA, in cerebrospinal fluid. We then examine in more detail the interaction of hyperammonemia and benzoate/ phenylacetate treatment on brain serotonin turnover in the chronically hyperammonemic ornithine transcarbamylase deficient sparse-fur (spf/y) mouse. METHODSBiochemical methods. Plasma ammonium was measured by a microfluorometric adaptation of a glutamate dehydrogenase method as previously d...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Effect of Sodium Benzoate and Sodium Phenylacetate on Brain Serotonin Turnover in the Ornithine Transcarbamylase-Deficient Sparse-Fur Mouse

et al. 1988

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“…This hypothesis is supported by the lack of correlation between the plasma concentrations of glutamine and tryptophan in urease-injected rats [17].…”

Section: Ammonia Large Neutral Amino Acids and Glutaminementioning

confidence: 96%

Ammonia toxicity to the brain and creatine

Bachmann

Braissant

Villard

et al. 2004

Molecular Genetics and Metabolism

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Symptoms of hyperammonemia are age-dependant; some are reversible.Multiple mechanisms are involved. Hyperammonemia increases the uptake of tryptophan into the brain by activation of the L-system carrier; brain glutamine plays a still undefined role. The uptake of tryptophan by the brain is enhanced if the levels of branched-chain amino acids competing with the other large neutral amino acids are low in plasma. Hyperammonemia increases the utilization of branched-chain amino acids in muscle when ketoglutarate is low;this is further enhanced with glutamine depletion (using phenylbutyrate). Anorexia, most likely a serotoninergic symptom, might further aggravate the deficiency of indispensable amino acids (branched-chain and arginine). The role of increased glutamine production in astrocytes and the excitotoxic and metabotropic effects of increased extracellular glutamate have been extensively described. They differ between models of acute and chronic hyperammonemia. Using an in vitro model of cultured embryonic rat brain cell aggregates, we studied the role of creatine. Cultures exposed to ammonia before maturation showed impaired cholinergic axonal growth accompanied by a decrease of creatine and phosphocreatine, a finding not seen in mature cultures. By using different antibodies we have shown that the phosphorylated form of the intermediate neurofilament protein is affected.Adding creatine to the culture medium partially prevents impairment of axonal growth. The presence of glia in the culture is a precondition for this protective effect. Adequate arginine substitution is essential in the treatment of urea cycle defects as creatine is inefficiently transported into the brain.3

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“…This is accomplished in the astrocyte via glutamine synthetase (GS). Glutamine is osmotically active and can cause astrocytic swelling leading to cytotoxic oedema (Batshaw et al 1986;Bender and Norenberg 1996;Norenberg 1996;Norenberg et al 2005). Studies in which the GS inhibitor methionine sulfoximine is administered demonstrate reduced ammonia-induced brain oedema in both in vivo (Takahashi et al 1991) and in vitro models (Blei et al 1994;Norenberg and Bender 1994;Takahashi et al 1991).…”

Section: Pathogenic Mechanisms Of Acute Hyperammonaemiamentioning

confidence: 99%

Neurological implications of urea cycle disorders

Gropman

Summar

Leonard³

2007

J of Inher Metab Disea

190

152

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SummaryThe urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular 1 H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate-nitric oxide-cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.

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Behavioral and Neurotransmitter Changes in the Urease-Infused Rat: A Model of Congenital Hyperammonemia

Cited by 39 publications

References 15 publications

Effect of Sodium Benzoate and Sodium Phenylacetate on Brain Serotonin Turnover in the Ornithine Transcarbamylase-Deficient Sparse-Fur Mouse

Effect of Sodium Benzoate and Sodium Phenylacetate on Brain Serotonin Turnover in the Ornithine Transcarbamylase-Deficient Sparse-Fur Mouse

Ammonia toxicity to the brain and creatine

Neurological implications of urea cycle disorders

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