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PubMed1990

Hyperammonemia induces brain tubulin.

We have developed an animal model of hyperammonemia consisting of feeding rats a diet containing ammonium acetate. Using this model we have found that hyperammonemia induces tubulin synthesis in brain. Initially tubulin accumulates rapidly (28% after 2 days on diet) and continues increasing but at a slower rate, reaching a 50% increase after 100 days on the diet. The effect is reversible, rats fed the ammonium diet return to normal levels of tubulin two days after withdrawal of the ammonium diet. In contrast to the effect on brain, hyperammonemia did not increase tubulin content in liver or kidney. Moreover, the effect on brain is selective, with maximum increases of tubulin content in hippocampus, septum and reticular formation while other areas such as locus coeruleus and mammillary nucleus are not affected at all. The results presented show that the induction of tubulin is a consequence of an increased polymerization of microtubules which in turn is due to an altered phosphorylation of microtubule-associated proteins.

Ammonia↗
PubMed1993

The two catalytic components of the 2-oxoglutarate dehydrogenase complex in rat cerebral synaptic and nonsynaptic mitochondria: comparison of the response to in vitro treatment with ammonia, hyperammonemia, and hepatic encephalopathy.

The effects of in vitro treatment with ammonium chloride, hepatic encephalopathy (HE) due to thioacetamide (TAA) induced liver failure and chronic hyperammonemia produced by i.p. administration of ammonium acetate on the two components of the multienzyme 2-oxoglutarate dehydrogenase complex (OGDH): 2-oxoglutarate decarboxylase (E1) and lipoamide dehydrogenase (E3), were examined in synaptic and nonsynaptic mitochondria from rat brain. With regard to E1 the response to ammonium ions in vitro (3 mM NH4Cl) was observed in nonsynaptic mitochondria only and was manifested by a 21% decrease of Vmax and a 35% decrease of Km for 2-oxoglutarate (2-OG). By contrast, both in vivo conditions primarily affected the synaptic mitochondrial E1: TAA-induced HE produced an 84% increase of Vmax and a 38% increase of Km for 2-OG. Hyperammonemia elevated Vmax of E1 by 110% and Km for 2-OG by 30%. HE produced no effect at all in nonsynaptic mitochondria while hyperammonemia produced a 35% increase of Vmax and a 30% increase of Km for 2-OG of E1. Both in vivo conditions produced a 20% increase of E3 activity in synaptic mitochondria, but no effect at all in nonsynaptic mitochondria. The preferential sensitivity of E1 to ammonium chloride in vitro in nonsynaptic mitochondria and hyperammonemic conditions in vivo in synaptic mitochondria may play a crucial role in the compartmentation of OGDH responses under analogous conditions. These results confirm the intrinsic differences between the OGDH properties in the synaptic and nonsynaptic brain compartments.

Acetates↗
PubMed1993

Changes in the cytoplasmic (lactate dehydrogenase) and plasma membrane (acetylcholinesterase) marker enzymes in the synaptic and nonsynaptic mitochondria derived from rats with moderate hyperammonemia.

The activities of the cytoplasmic and plasma membrane marker enzymes: lactate dehydrogenase (LDH) and acetylcholinesterase (AChE), respectively, were measured in the cerebral homogenates, in the synaptic and nonsynaptic mitochondrial fractions, and in the postmitochondrial supernatants derived from rats in which a 3-d, moderately hyperammonemic condition (no more than 120% increases in blood ammonia) was produced by repeated administration of ammonium acetate (simple hyperammonemia, SHA) or a hepatotoxin, thioacetamide (TAA) (hepatic encephalopathy, HE). As measured in the homogenate and postmitochondrial supernatants, neither of the enzyme activities was affected by SHA or HE. SHA and HE increased the synaptic mitochondrial LDH activity by respectively 53 and 24%, but reduced this enzyme activity in nonsynaptic mitochondria by 19%. Both conditions stimulated the synaptic and nonsynaptic mitochondrial AChE activity by 30-40%. By contrast, the only significant change produced in these fractions by in vitro treatment with a toxic (3 mM) concentration of ammonium chloride was a slight decrease of LDH activity in nonsynaptic mitochondria and postmitochondrial supernatants. It is concluded that moderate hyperammonemia modifies subsequent separation of both cerebral classes of mitochondria from the cytosolic and plasma membrane components. This modification is likely to reflect subtle hyperammonemia-related changes in the physicochemical properties of the two mitochondrial classes and/or other subcellular components.

Acetylcholinesterase↗
PubMed1991

Decreased potassium-stimulated release of [3H]D-aspartate from hippocampal slices distinguishes encephalopathy related to acute liver failure from that induced by simple hyperammonemia.

The calcium-dependent, high (65 mM) potassium-evoked release of the L-glutamate analogue [3H]D-aspartate (D-Asp) was measured in hippocampal slices derived from rats with (a) hepatic encephalopathy (HE) induced with a hepatotoxin, thioacetamide, (b) hyperammonemia produced by i.p. administration of ammonium acetate, and (c) in normal slices preincubated for 30 min with 1 mM ammonium acetate. HE (variant a) inhibited the release by about 30%, which was interpreted to indicate depressed exocytosis of synaptic glutamate. This phenomenon is likely to lead to a decrease of glutamate-mediated neural excitation, which in turn could contribute to the neural inhibition typical of HE. By contrast, and in agreement with earlier reports, hyperammonemia (variant b) did not affect D-Asp release, whereas in vitro treatment of the slices with ammonium acetate (variant c) resulted in a 60% increase of the release. Hence, impairment of synaptic glutamate exocytosis is the phenomenon that distinguishes HE related to toxic liver failure from simple hyperammonemia. This result emphasizes the role of other factors than ammonia in the pathophysiological mechanism of HE.

Acetates↗
PubMed1995

The benzodiazepine antagonist CGS 8216 prevents hyperammonemia-induced somatostatin receptor reduction in the brain.

Previous results from our group showed that hyperammonemia decreases the number of somatostatin (SS) receptors and that benzodiazepine receptors might regulate the number of SS receptors in rat brain. These findings together with the supersensitivity of benzodiazepine receptors in the hyperammonemic rat brain suggest that benzodiazepine receptors might mediate the effect of hyperammonemia on SS receptors. To assess this hypothesis we tested whether 2-phenylpyrazolo[3,4-c]-quinolin-3(5H)-one (CGS 8216), a benzodiazepine antagonist, prevented the effect of ammonium acetate on rat brain SS receptors. Administration of ammonium acetate (5 mmol/kg, i.p.) for 7 days did not affect the levels of somatostatin-like immunoreactivity but decreased the number of SS receptors in synaptosomes from the frontoparietal cortex and hippocampus without affecting their apparent affinity. This decrease could be blocked by the concomitant administration of CGS 8216 (10 mg/kg, i.p.). The benzodiazepine antagonist alone had no observable effect on the somatostatinergic system. These results suggested that the effect of hyperammonemia on SS receptors could be mediated, at least in part, through the benzodiazepine receptors.

Ammonia↗
PubMed1980

Urinary purines and pyrimidines in patients with hyperammonemia of various origins.

Excretion patterns of pyrimidines and purines in patients with various types of hyperammonemia have been investigated by 2-dimensional thin-layer chromatography and high pressure liquid chromatography (HPLC). For the quantitative analysis of pseudouridine, uracil and uridine a new procedure has been developed, consisting of pre-fractionation with Dowex 1 X 8, followed by dual column HPLC on a strong anion-exchanger and a reverse phase column. Thymine has also been analyzed in the pre-fractionated urine by a new HPLC method using the reverse phase column in combination with a strong cation-exchange column. Quantitative data for urinary pyrimidines and uric acid in hyperammonemia are given. In patients with a defect in one of the urea cycle enzymes, the level of pyrimidine excretion was found to depend on plasma ammonia concentrations. In other hyperammonemic patients, an increased excretion of orotic acid, uracil and uridine has only been found in one of the two patients with lysinuric protein intolerance, all other patients showing normal excretion patterns. Elevated uric acid excretions have been found frequently in our patients with hyperammonemia, but they did not always coincide with high plasma ammonia levels. A possible explanation for the difference in the excretion levels of the various pyrimidines is discussed.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

Hyperammonemia caused by impaired mitochondrial ornithine transport in a patient with partial quantitative deficiency of ornithine carbamoyltransferase.

Late-onset hyperammonemia was observed in a male patient with partial quantitative deficiency of ornithine carbamoyltransferase (OCT). His liver contained 10% of the normal level of OCT, but with normal kinetics. This reduced enzyme activity alone, however, could not explain the hyperammonemia. Therefore, the effects of impaired ornithine transport into mitochondria, which seemed to be a possible precipitating factor, were examined by numerical simulation of the urea cycle. The results were as follows: (a) On the assumption that the ornithine concentrations in the cytosol and mitochondrial matrix were always equal, the ammonia handling efficiency would be unchanged by decrease in the OCT concentration to 10% of normal; (b) Under conditions of impaired mitochondrial ornithine transport that had no effects on ureagenesis with a normal amount of enzyme, 10% of the normal concentration of enzyme would impair ammonia handling efficiency. Thus, impaired mitochondrial ornithine transport seemed to cause hyperammonemia in the state of partial quantitative deficiency of OCT in this case.

Adolescent↗
PubMed1992

Altered glutamine metabolism in rat portal drained viscera and hindquarter during hyperammonemia.

In normal rats, muscle is the major glutamine releasing organ and gut is the major glutamine consuming organ. It has been suggested that enhanced muscle ammonia detoxification and gut ammonia production occurs during liver insufficiency-induced hyperammonemia. Therefore, ammonia and amino acid fluxes across portal-drained viscera and hindquarter, and muscle concentrations were measured in portacaval shunted and acute liver ischemia rats. Arterial ammonia and most amino acids were increased after portacaval shunting and increased progressively during liver ischemia, but net hindquarter ammonia uptake was not observed. Net hindquarter glutamine efflux was increased during portacaval shunting, but it decreased during liver ischemia, while muscle glutamine concentrations increased. The comparable net portal drained viscera glutamine uptake in normal and portacaval shunted rats changed during liver ischemia from net uptake to release, coinciding with release of most other amino acids. These results cast doubt on the ammonia detoxifying role of muscle during acute liver ischemia-induced hyperammonemia in the rat. The portal drained viscera glutamine release during severe hyperammonemia could be due to intestinal damage.

Amino Acids↗
PubMed1985

Decrease of valproate-induced hyperammonemia in normal subjects by lipid ingestion.

Sodium valproate (VPA), a branched short-chain fatty acid, always causes a hyperammonemia of renal origin in fasting man. The intake of medium-length, straight-chain fatty acids abolishes the VPA-induced hyperammonemia, and VPA free fraction increases concomitantly. Accordingly, fatty acids could be useful in preventing and treating hyperammonemia-accompanied stuporous states which are complications of VPA medication.

Ammonia↗
PubMed1989

Hyperammonemia, increased brain neutral and aromatic amino acid levels, and encephalopathy induced by cyanide in mice.

The correlation among hyperammonemia, brain neutral amino acid, and encephalopathy induced by cyanide was investigated in mice. Subcutaneous injection of 10 mg/kg of potassium cyanide increased the levels of blood ammonia by 2.5-fold as compared to those of the corresponding controls and caused loss of consciousness in 100% of the treated mice. alpha-Ketoglutarate (500 mg/kg, ip) completely blocked the development of loss of consciousness and hyperammonemia induced by cyanide. Furthermore, the same doses of potassium cyanide increased by 50-150% the levels of brain neutral and aromatic amino acids such as leucine, isoleucine, tyrosine, and phenylalanine, while the levels of acidic amino acid such as taurine, glutamate, and aspartate did not change. alpha-Ketoglutarate also significantly inhibited the increase of the neutral and aromatic amino acid levels in brain. These findings suggest that the hyperammonemia and the increase of neutral and aromatic amino acids may play an important role in development of loss of consciousness induced by cyanide.

Adenosine Triphosphate↗
PubMed1988

Hepatic ATP content and hyperammonemia induced by CCl4 in rats.

An investigation of the mechanism of development of hyperammonemia observed in CCl4-induced hepatic encephalopathy was performed in rats. CCl4 (1.0 ml/kg 3 times per week for over 10 weeks) caused a severe hyperammonemia and depletion of hepatic ATP contents in only those rats with hepatic encephalopathy. However, CCl4 (1.0 ml/kg 3 times per week for 7 weeks) did not cause hepatic encephalopathy and did not change in blood ammonia levels. Administration of 2,4-dinitrophenol (2,4-DNP) in these CCl4-treated rats caused hepatic encephalopathy within 30 min after injection and then the increase of 140 micrograms/dl in blood ammonia levels and the decrease of 80% in hepatic ATP contents were observed. However, the administration of 2,4-DNP in CCl4-untreated rats did not cause hepatic encephalopathy within 30 min after injection although the increase of 70 micrograms/dl in blood ammonia levels and the decrease of 80% in hepatic ATP contents were observed. Hepatic activities of carbamylphosphate synthetase (CPS) and argininosuccinate synthetase (ASS), important enzymes of the urea cycle, were significantly inhibited by 85% and 60% respectively, in rats treated with CCl4 plus 2,4-DNP. However, in rats treated with 2,4-DNP and without CCl4, the hepatic activities of CPS and ASS were inhibited only 25% and 0%, respectively. These findings suggest that the severe hyperammonemia, which may be produced by the decrease of hepatic ATP content and the inhibition of CPS and ASS, may play an important role in induction of hepatic encephalopathy.

2,4-Dinitrophenol↗
PubMed1993

Effect of repeated hyperammonemia on Na(+)-dependent binding of glutamate in rat cortical and hippocampal synaptic membranes.

Na(+)-dependent binding of L-glutamate in cortical and hippocampal synaptic membranes from hyperammonemic rats was compared to corresponding data in the controls. In hippocampal membranes, repeated hyperammonemia resulted in a 13% and 18% decrease in binding in 20-day-old and 50-day-old rats, respectively. The decrease was statistically significant (P < 0.05) in the older animals and Scatchard analysis revealed a 19% reduction in the number of binding sites without any changes in the affinity. Within the hippocampal formation, the binding in the dentate gyrus was the most sensitive to hyperammonemia where a 21% decrease was found (P < 0.01), whilst the decline of binding in CA1 and CA3 areas of the hippocampus proper was not significant. The results support the idea that excessive accumulation of extracellular glutamate during hyperammonemia is a consequence not only of its increased release, but also of the blocking of Na(+)-dependent binding of glutamate to specific uptake sites.

Aging↗
PubMed1997

Fatal hyperammonemia following orthotopic lung transplantation.

There have been anecdotes of unexplained coma and death in patients after otherwise successful orthotopic lung transplantation. A patient with primary pulmonary hypertension who underwent a technically uncomplicated single orthotopic lung transplantation is described. The patient developed intractable status epilepticus 4 days after surgery in association with the presence of a markedly elevated plasma ammonium level. Despite multiple therapeutic interventions, the hyperammonemia ultimately resulted in the patient's death. Both metabolic and enzymatic studies showed that the unique physiological disturbance in this disorder results at least in part from defective in vivo conversion of waste nitrogen to urea and increased production of waste nitrogen. Although the rate of hepatic ureagenesis was therefore insufficient to prevent accumulation of ammonium, the cause was not severe liver disease. Liver histology showed widespread, microvesicular steatosis on light-microscopic examination, but only electron-microscopic examination showed severe microvesicular steatosis with severe mitochondrial injury. As in Reye's syndrome, it was unclear whether the hepatic mitochondrial injury played a role in development or if it was the result of hyperammonemia. We recommended that any patient with an unexplained alteration of mental status after solid organ transplantation be evaluated for hyperammonemia.

Ammonia↗
PubMed1995

Neonatal hyperammonemia caused by a defect of carnitine-acylcarnitine translocase.

Carnitine-acylcarnitine translocase deficiency is a newly recognized inborn error of metabolism that involves transport of long-chain fatty acids into mitochondria, which in turn impairs mitochondrial beta-oxidation, and ketogenesis. We report a new familial example; the affected twins had neonatal distress, hyperammonemia, and transient intracardiac conduction defects. Clinical and biochemical analysis of both our patients and the two previously reported patients revealed that this inherited defect could be manifested during the neonatal period without any of the signs classically associated with fatty oxidation defects. In contrast, all four patients had sustained and "isolated" hyperammonemia, which could be misinterpreted as being caused by urea cycle defects. We conclude that carnitine-acylcarnitine translocase deficiency is a potential differential diagnosis in neonates with unexplained neonatal hyperammonemia. Cardiac and muscle involvement may represent further early pivotal symptoms.

Ammonia↗
PubMed1999

Reduction in the MK-801 binding sites of the NMDA sub-type of glutamate receptor in a mouse model of congenital hyperammonemia: prevention by acetyl-L-carnitine.

Our earlier studies on the pharmacotherapeutic effects of acetyl-L-carnitine (ALCAR), in sparse-fur (spf) mutant mice with X linked ornithine transcarbamylase deficiency, have shown a restoration of cerebral ATP, depleted by congenital hyperammonemia and hyperglutaminemia. The reduced cortical glutamate and increased quinolinate may cause a down-regulation of the N-methyl-D-aspartate (NMDA) receptors, observed by us in adult spf mice. We have now studied the kinetics of [3H]-MK-801 binding to NMDA receptors in spf mice of different ages to see the effect of chronic hyperammonemia on the glutamate neurotransmission. We have also studied the Ca2+-dependent and independent (4-aminopyridine (AP) and veratridine-mediated) release of glutamate and the uptake of [3H]-glutamate in synaptosomes isolated from mutant spf mice and normal CD-1 controls. All these studies were done with and without ALCAR treatment (4 mmol/kg wt i.p. daily for 2 weeks), to see if its effect on ATP repletion could correct the glutamate neurotransmitter abnormalities. Our results indicate a normal MK-801 binding in 12-day-old spf mice but a significant reduction immediately after weaning (21 day), continuing into the adult stage. The Ca2+-independent release of endogenous glutamate from synaptosomes was significantly elevated at 35 days, while the uptake of glutamate into synaptosomes was significantly reduced in spf mice. ALCAR treatment significantly enhanced the MK-801 binding, neutralized the increased glutamate release and restored the glutamate uptake into synaptosomes of spf mice. These studies point out that: (a) the developmental abnormalities of the NMDA sub-type of glutamate receptor in spf mice could be due to the effect of sustained hyperammonemia, causing a persistent release of excess glutamate and inhibition of the ATP-dependent glutamate transport, (b) the modulatory effects of ALCAR on the NMDA binding sites could be through a repletion of ATP, required by the transporters to efficiently remove extracellular glutamate.

Acetylcarnitine↗
PubMed1999

Hyperammonemia: regulation of argininosuccinate synthetase and argininosuccinate lyase genes in aggregating cell cultures of fetal rat brain.

Hyperammonemia in the brain leads to poorly understood alterations of nitric oxide (NO) synthesis. Arginine, the substrate of nitric oxide synthases, might be recycled from the citrulline produced with NO by argininosuccinate synthetase (AS) and argininosuccinate lyase (AL). The regulation of AS and AL genes during hyperammonemia is unknown in the brain. We used brain cell aggregates cultured from dissociated telencephalic cortex of rat embryos to analyze the regulation of AS and AL genes in hyperammonemia. Using RNase protection assay and non-radioactive in situ hybridization on aggregate cryosections, we show that both AS and AL genes are induced in astrocytes but not in neurons of aggregates exposed to 5 mM NH4Cl. Our work suggests that the hyperammonemic brain might increase its recycling of citrulline to arginine.

Ammonia↗
PubMed1997

Diet- and valproate-induced transient hyperammonemia: effect of L-carnitine.

Hyperammonemia is an adverse effect of valproate (VPA) treatment. In particular, transient hyperammonemia has been reported to occur in VPA-treated patients after protein-rich meals. This phenomenon may occur secondary to a VPA-mediated carnitine insufficiency. We sought to confirm that protein ingestion would result in transient hyperammonemia and to determine whether supplementation with L-carnitine would prevent this effect. We studied the effect of consumption of a standardized protein-rich meal (45 g protein) before (phase I) and after (phase II) administration of L-carnitine 50 mg/kg/day for 7 days in 11 epileptic children (13.3 +/- 2.3 years of age) receiving VPA. Venous blood was obtained during fasting (baseline) and at 2 and 4 hours after the protein-rich meal for analysis of ammonia (NH3), and VPA concentrations. Mean VPA trough concentrations did not differ significantly at any time. After protein ingestion, 2-hour NH3 concentration increased by 86% (P < .05) from baseline in phase I as compared with a 38% increase in phase II. In both phases I and II, 4-hour NH3 concentrations decreased toward baseline values. We conclude that (1) modest protein ingestion can result in significant transient increases in NH3 in VPA-treated children, (2) significant increases may occur in patients with normal fasting NH3 concentrations, (3) these increases can be significantly attenuated by L-carnitine supplementation, and (4) these changes do not appear to be related to changes in VPA concentration.

Administration, Oral↗
PubMed1998

Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo.

The aim of this work was to assess whether ammonia concentrations similar to the increase found in the brain of hyperammonemic rats (100 microM), impair N-methyl-D-aspartate (NMDA) receptor-mediated signal transduction. We first measured glutamate neurotoxicity, which in these neurons is mediated by activation of NMDA receptors, as an initial parameter reflecting activation of NMDA receptor-mediated pathways. Long-term treatment of cultured neurons with ammonia prevents glutamate-induced neuronal death. The EC50 was 20 microM, and at 100 microM the protection was complete. The induction of the protective effect was not immediate, but took several hours. Treatment with 100 microM ammonia did not prevent a glutamate- or NMDA-induced rise of intracellular calcium. Ammonia impaired the glutamate-nitric oxide-cGMP (3',5'-cyclic guanosine monophosphate) pathway in a dose- and time-dependent manner. Glutamate-induced formation of cGMP was reduced by 42%, while activation of nitric oxide synthase was not affected. Ammonia reduced by 31% cGMP formation induced by S-nitroso-N-acetyl-penicillamine (SNAP), a NO-generating agent, confirming that the interference occurs at the level of guanylate cyclase activation by nitric oxide. To assess whether chronic moderate hyperammonemia in vivo also impairs the glutamate-nitric oxide-cGMP pathway, we determined by in vivo brain microdialysis in freely moving rats the formation of cGMP induced by NMDA. In hyperammonemic rats, the formation of cGMP induced by NMDA and SNAP was reduced by ca. 60 and 41%, respectively, indicating that chronic hyperammonemia in the animal in vivo also impairs the glutamate-nitric oxide-cGMP pathway. Impairment of this pathway can contribute to the neurological alterations found in hyperammonemia and hepatic encephalopathy.

Ammonia↗