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PubMed1985

Disruption of the blood-brain barrier in hyperammonemic coma and the pharmacologic effects of dexamethasone and difluoromethyl ornithine.

Both hyperammonemia and blood-brain barrier (BBB) breakdown have been implicated in the evolution of hepatic encephalopathy. To define a possible relationship, Swiss Albino mice were subjected to sublethal encephalopathic doses of ammonium acetate; the integrity of the BBB was determined grossly with Evans blue and quantitatively with [14C]-alpha-aminoisobutyrate (AIB). Some animals were injected with a dose of ammonium acetate sufficient to maintain coma for 1 hr (AC group). One group, termed stuporous (AS), received only enough ammonium acetate to interfere with grooming and exploratory activity; this dosage was insufficient to completely block the righting response, which was absent in the AC group. When compared to that of controls (CON) receiving normal saline instead of ammonium acetate, cerebral tissue from the AC group was stained blue and contained nearly double the amount of AIB; AS group brain tissue was unstained and the AIB content did not differ significantly from normal. Some of the AC group were pretreated with drugs known to retard BBB breakdown; one set received dexamethasone (AC-DXMN), another the ornithine decarboxylase inhibitor difluoromethyl ornithine (AC-DFMO), and a third L-ornithine (AC-ORN). Brain tissue from the AC-ORN group stained blue and AIB content did not differ significantly from that of the untreated AC group. Cerebral tissue of the AC-DXMN pretreatment group stained light blue; AIB content was significantly lower than in the AC group and greater than the CON group. The AC-DFMO brains were unstained and AIB content was significantly lower than in the AC group but did not differ significantly from CON. These results indicate that hyperammonemia may induce BBB breakdown but that the disruption of barrier integrity is not antecedent to the development of coma, although it seems to coincide with coma in time.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗

PubMed1992

Biological activity of urease formulated in poloxamer 407 after intraperitoneal injection in the rat.

The advent of genetic engineering has resulted in a proliferation of protein pharmaceuticals available for a variety of therapeutic needs. However, the formulation and delivery of these proteins remain an intriguing challenge. Polymer-based protein drug delivery systems continue to be investigated, although many of the fabrication techniques used to incorporate proteins into the polymer matrix or device result in irreversible inactivation (denaturation) of the proteins. A well-characterized model enzyme, urease, was formulated in 33% (w/w) poloxamer 407 (Pluronic F-127) vehicle and injected intraperitoneally (ip) into rats in an attempt to achieve both preservation of biological activity and sustained release of the protein. The resulting ammonia concentration in plasma-time profiles were compared with those for rats injected with an identical dose (27.6 units of activity per 200 g of body weight) of urease dissolved in pH 7 phosphate buffer. Neither a pH 7 phosphate buffer solution nor poloxamer 407 (33%, w/w) dissolved in pH 7 phosphate buffer, when injected ip into rats, resulted in elevated ammonia levels in plasma. The time to reach a maximum ammonia level in plasma was increased approximately threefold following the injection of the urease-poloxamer 407 formulation, compared with that in control rats administered an identical dose of urease in solution. In addition, hyperammonemia was extended almost threefold in treated rats compared with control rats, without untoward effects. However, prolonged hyperammonemia in animals receiving an ip injection of the urease-poloxamer 407 formulation may have potentially resulted from the reduced clearance of ammonia and ammonium ion in the proximal tubules of the rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonia↗

PubMed2005

MARS treatment for a patient presenting with acquired hepatic glutamine synthetase deficiency after orthotopic liver transplantation.

We report a 48-year-old man presenting with refractory hyperammonemia after orthotopic liver transplantation. On investigation he was found to have acquired hepatic glutamine synthetase deficiency, a rare condition that occurs after organ transplantations. The patient was started on continuous venovenous hemofiltration treatment, but the hyperammonemia did not respond. The patient was then subjected to molecular adsorption recirculation system (MARS) therapy and the ammonia level gradually improved with successive treatments. In conclusion, the response was unlikely due to the hemofiltration component of MARS alone but more probably due to the removal of putative albumin-bound toxin by the adsorption circuit that had ameliorated the internal milieu of the graft and reversed the enzyme deficiency.

Bilirubin↗

PubMed1991

What the clinician can learn from MR glutamine/glutamate assays.

At present in vivo NMR spectroscopic studies of brain glutamate and glutamine concentrations relative to encephalopathy have mainly been performed in hepatic encephalopathy (HE). In vivo proton NMR studies were performed in rats with hyperammonemia and acute HE due to acute liver ischemia as well as in rats with hyperammonemia due to either repeated urease i.p. injection or i.p. administration of methionine sulfoximine, a well known inhibitor of glutamine synthetase. In man, in vivo proton NMR is described in patients with chronic liver disease: cirrhosis of different etiology and associated with different degrees of HE. In the experimental models proton NMR spectroscopy of the cerebral cortex revealed an increase in glutamine concentration, a decrease in glutamate concentration and a decrease in phosphocholine compounds. In humans no clear distinction between cerebral cortex glutamate and glutamine concentration could be made by in vivo 1H NMR spectroscopy. However, the combined glutamate/glutamine peak increased in a way compatible with an increased cerebral cortex glutamine concentration during chronic HE. In the cirrhotic patients too a decrease in cerebral cortex phosphocholine compounds was observed, the explanation of which is unclear. Both the experimental work and the clinical observations support the hypothesis that impairment of the glutamate/glutamine cycle between astrocytes and neurons plays a role in the pathogenesis of hepatic encephalopathy.

Animals↗

PubMed1995

Free and esterified coenzyme A in the liver and muscles of chronically hyperammonemic mice treated with sodium benzoate.

Ammonia toxicity and relative sodium benzoate toxicity alters the energy metabolism, leading to a decrease of adenosine triphosphate and free coenzyme A levels. The object of the present study was to analyze the hepatic and muscular acyl-coenzyme A profiles in chronically hyperammonemic mice treated with varying doses of the sodium benzoate. An enzymatic method was used for the measurement of free coenzyme A, acetyl-coenzyme A, and medium and long chain acyl-coenzyme A. Untreated chronic hyperammonemia resulted in a decrease in acetyl-coenzyme A and an increase in the long chain acyl-coenzyme A in the liver, accompanied by an increase in total coenzyme A in the muscular tissues. Treatment with sodium benzoate at moderate doses, caused a decrease in the hepatic free and esterified coenzyme A while these were increased at higher doses. We conclude that chronic hyperammonemia is responsible for qualitative changes in the free and esterified coenzyme A profile in the liver, while causing qualitative and quantitative changes in the muscular tissue, probably due to an inhibition of mitochondrial oxidation. The sodium benzoate had a biphasic effect on the hepatic content of free and esterified coenzyme A, suggesting a degradation of coenzyme A at moderate doses. However, at a higher dose of benzoate, the possibility of glycine mobilization and/or a significant formation of acylcarnitines is proposed as an important factor in an increase of the hepatic total coenzyme A.

Acetyl Coenzyme A↗

PubMed1997

Inhibition of carbamyl phosphate synthetase-I and glutamine synthetase by hepatotoxic doses of acetaminophen in mice.

The primary mechanisms proposed for acetaminophen-induced hepatic necrosis should deplete protein thiols, either by covalent binding and thioether formation or by oxidative reactions such as S-thiolations. However, in previous studies we did not detect significant losses of protein thiol contents in response to administration of hepatotoxic doses of acetaminophen in vivo. In the present study we employed derivatization with the thiol-specific agent monobromobimane and separation of proteins by SDS-PAGE to investigate the possible loss of specific protein thiols during the course of acetaminophen-induced hepatic necrosis. Fasted adult male mice were given acetaminophen, and protein thiol status was examined subsequently in subcellular fractions isolated by differential centrifugation. No decreases in protein thiol contents were indicated, with the exception of a marked decrease in the fluorescent intensity, but not of protein content, as indicated by staining with Coomassie blue, of a single band of approximately 130 kDa in the mitochondrial fractions of acetaminophen-treated mice. This protein was identified by isolation and N-terminal sequence analysis as carbamyl phosphate synthetase-I (CPS-I) (EC 6.3.4.16). Hepatic CPS-I activities were decreased in mice given hepatotoxic doses of acetaminophen. In addition, hepatic glutamine synthetase activities were lower, and plasma ammonia levels were elevated in mice given hepatotoxic doses of acetaminophen. The observed hyperammonemia may contribute to the adverse effects of toxic doses of acetaminophen, and elucidation of the specific mechanisms responsible for the hyperammonemia may prove to be useful clinically. However, the preferential depletion of protein thiol content of a mitochondrial protein by chemically reactive metabolites generated in the endoplasmic reticulum presents a challenging and potentially informative mechanistic question.

Acetaminophen↗

PubMed1993

Cerebral metabolic studies in vivo by combined 1H/31P and 1H/13C NMR spectroscopic methods.

Intracellular pH and ammonium ion concentration are potent modulators of cerebral amino acid metabolism. Furthermore, intracellular acidosis and hyperammonemia accompany conditions such as ischemic encephalopathy and seizures and may contribute to the pathological sequelae observed. In vivo NMR spectroscopy permits multiple, non-destructive measurements of important cerebral metabolic intermediates in the same animal. We describe here the use of 1H, and 31P NMR spectroscopy to investigate the effects of acute changes in intracellular pH and ammonium ions on cerebral glutamate, glutamine, and lactate levels in vivo. We then show how 1H NMR can be used to indirectly follow the flow of 13C label from [1-13C] glucose into the cerebral glutamate pool, allowing us to measure cerebral TCA activity in normal and chronically hyperammonemic rats. Male Sprague-Dawley rats (160-210 gm), fasted 24-hours, were tracheotomized, paralyzed and ventilated on 30% O2/70% N2O. NMR spectroscopy was performed at a field strength of 8.4 Tesla using a Bruker AM-360 wide bore spectrometer. An elliptical surface-coil (8 x 12 mm) was double-tuned to either the 1H and 31P or 1H and 13C frequencies. After retraction of extracranial tissues, the coil was positioned over the skull 2 mm posterior to the bregma. Tail arteries and veins were cannulated allowing periodic measurements of PO2, pCO2, pH and glucose in arterial blood and intravenous infusions. Respiratory acidosis was induced in rats by the addition of CO2 to the ventilation gas mixture. Arterial pCO2 increased within 5 min from a pre-hypercarbic value of 36.4 +/- 6.1 mm Hg to 200-220 mm Hg and was maintained at this level for over 1 hour. Hypercarbia led to rapid cerebral acidification. Intracellular pH decreased from 7.18 +/- 0.08 (pre-hypercarbic period) to 6.68 +/- 0.06 (n = 4) at 10 min and remained stable throughout the NMR observation period. Glutamate decreased to 53 +/- 4% of control after 60 min of hypercarbia, while glutamine increased to 126 +/- 7% of control. Acute hyperammonemia was produced by a programmed intravenous infusion of 250 mM ammonium acetate, which rapidly raised and maintained the concentration of ammonium ions in the blood at approximately 500 microM. Shortly after the start of the infusion (10-20 min), the levels of glutamine and lactate rose continuously throughout the experiment, reaching levels of 170 +/- 25% and 260 +/- 60% of control, respectively (n = 12) after 50 min. Glutamate decreased during the same time interval to 80 +/- 4% of control (n = 12).(ABSTRACT TRUNCATED AT 400 WORDS)

Acid-Base Equilibrium↗

PubMed1981

Neonatal glutaric aciduria type II: an X-linked recessive inherited disorder.

A new case of neonatal glutaric aciduria type II is reported. Neonatal acidosis, hypoglycemia, and hyperammonemia were characteristic. The baby died at four days of age. Organic acid analysis revealed massive glutaric aciduria with elevated concentrations of butyric, isobutyric, n-butyric, and isovaleric acid in his urine. The baby's pedigree suggested strongly an X-linked recessive mode of inheritance. Clinically, biochemically, and genetically glutaric aciduria type II is an heterogeneous disorder. The neonatal form is an X-linked inherited disorder which presents early in life, and is associated with metabolic acidosis, hypoglycemia, and hyperammonemia, and leads to death in the neonatal period. The mild form is an autosomal recessive inherited disease which may present even in adults, and is associated with recurrent hypoglycemia without ketosis and usually improves. Nevertheless the same unusual organic acid pattern is observed in both forms. The basic biochemical defect must be distinct and has not been elucidated.

Acidosis↗

PubMed1975

Diabetogenic effect and inhibition of insulin secretion induced in normal rats by ammonium infusions.

In order to explain the abnormalities of glucose metabolism previously observed in patients with blood ammonia elevation, the effect of a transitory hyperammonemia on I.V. glucose tolerance was investigated in rats. An I.V. glucose tolerance test was performed in 3 groups of 15 rats 60 min after the beginning of a 95 min infusion of either a 2 ml isotonic NaCl solution (control group) or ammonium acetate solutions at low (0.50 mumol/kg/min. NH4+) or high doses (1.70 mumol/kg/min NH4+). The "high" NH4+ infusion produced an increase of blood ammonia to levels near 1000 mug/100 ml, a significant decrease in the K coefficient for glucose disappearance (2.53 X 10(-2) +/- 0.20 compared to 4.92 X 10(-2) +/- 0.13 in control group) and a suppression of the radioimmunological plasma insulin (I.R.I.) response to glucose. With the "low" NH4+ infusion the hyperammonemia was less pronounced (200-300) mug/100 ml), but the decrease in K(3.02 X 10(-2) +/- 0.15) and in the first phase of I.R.I. release remained significant. The decrease in glucose disappearance rate could be accounted for by the proportional decrease in insulin secretion. Thus glucose intolerance induced by ammonium acetate infusions may be due to a direct effect of NH4 + on the pancreas. These abnormalities in glucose metabolism depend on the quantity of infused ammonium.

Acetates↗

PubMed1977

Experimental spongy degeneration in calves.

Experimental reproduction and ultrastructural findings of spongy degeneration of the central nervous system of hyperammonemic calves are described. Hyperammonemia was produced by intravenous infusion of ammonium acetate. Histologic findings were stereotyped in all calves and characterized by widespread vacuolation of white and grey matter of the brain spinal cord. Electron microscopy revealed widespread intramyelinic vacuoles, some expansion of extracellular spaces and swollen mitochondria. There were minimal changes in neurons, axons and glia, and little evidence of myelin breakdown. Hyperammonemia may be one of the pathogeneses involved in the CNS spongy degeneration in man and domestic animals effected with hepatocerebral diseases and some hereditary disorders.

Animals↗

PubMed1993

Is ammonia a pathogenetic factor in Alzheimer's disease?

An attempt was made to review experimental evidence in favor of the idea that ammonia plays a role in dementia of the Alzheimer type (DAT). Hyperammonemia causes biochemical and cellular dysfunctions in the brain, which can be found in brains of DAT patients. The most conspicuous among these findings are astrocytosis, impairment of glucose utilization, and a decreased rate of energy metabolism, and the impairment of neurotransmission, with a net increase in excitability and glutamate release. The derangement of lysosomal processing of proteins is another potential site of ammonia action. This aspect is especially important in view of the growing evidence for the role of the endosomal-lysosomal system in the formation of amyloidogenic fragments from beta-amyloid precursor protein. Ammonia is not considered a primary factor of the disease. However, since hyperammonemia and release of ammonia from the brains of DAT patients is well supported by published observations, ammonia should be taken into account as a factor that contributes to manifestations and the progression of DAT. If elevated ammonia concentrations turn out to be indeed as important in DAT, as is suggested in this review, rational therapeutic avenues can be envisaged that lead to the amelioration of symptoms and progression of the disease.

Alzheimer Disease↗

PubMed1995

Regional alterations of dopamine and its metabolites in rat brain following portacaval anastomosis.

Hyperammonemia and changes in brain monoamine metabolism have been proposed to contribute to the pathogenesis of the neuropsychiatric symptoms characteristic of human portal-systemic encephalopathy (PSE) resulting from chronic liver disease. Portacaval anastomosis (PCA) in the rat leads to sustained hyperammonemia and mild encephalopathy. In order to evaluate the role of dopamine (DA) metabolism in PSE, levels of DA and its metabolites were measured by HPLC with electrochemical detection in brain regions of rats with PCA at various stages of encephalopathy precipitated by ammonium acetate administration. Following ammonium acetate administration, rats with PCA rapidly develop severe neurological signs of encephalopathy progressing through loss of righting reflex to coma; sham-operated control animals administered ammonium acetate showed no such neurological deterioration. Concentrations of the DA metabolites DOPAC and HVA as well as [DA metabolites]/[DA] ratios, an indirect measure of DA turnover in brain, were increased in caudate-putamen, in cingulate and pyriform entorhinal cortices as well as in raphe nucleus and locus coeruleus. Increased DA metabolites, however, did not worsen at coma stages of PSE. Increased DA turnover thus appears to relate to early neuropsychiatric and extrapyramidal symptoms of PSE.

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

Cerebral ammonia metabolism in normal and hyperammonemic rats.

Brain ammonia is generated from many enzymatic reactions, including glutaminase, glutamate dehydrogenase, and the purine nucleotide cycle. In contrast, the brain possesses only one major enzyme for the removal of exogenous ammonia, i.e., glutamine synthetase. Thus, following administration of [13N]ammonia to rats [via either the carotid artery or cerebrospinal fluid (csf)], most metabolized label was in glutamine (amide) and little was in glutamate (plus aspartate). Since blood-and csf-borne ammonia are converted to glutamine largely, if not entirely, in the astrocytes, it is not possible from these types of experiments to predict with certainty the metabolic fate of the bulk of endogenously produced ammonia. By comparing the specific activity of L-[13N]glutamate to that of L-[amine-13N]glutamine following intracarotid [13N]ammonia administration it was concluded that metabolic compartmentation is no longer intact in the brains of rats treated with the glutamine synthetase inhibitor L-methionine-SR-sulfoximine (MSO) and that blood and brain ammonia pools mix in such animals. In MSO-treated animals, recovery of label in brain was low (approximately 20% of controls), and of the label remaining, a prominent portion was in glutamine (amide) (despite an 87% decrease in brain glutamine synthetase activity). These data are consistent with the hypothesis that glutamine synthetase is the major enzyme for metabolism of endogenously--as well as exogenously--produced ammonia. The rate of turnover of blood-derived ammonia to glutamine in normal rat brain is extremely rapid (t1/2 less than or equal to 3 s), but is slowed in the brains of chronically (12-14-wk portacaval-shunted) or acutely (urease-treated) hyperammonemic rats (t1/2 less than or equal to 10 s). The slowed turnover rate may be caused by an increased astrocytic ammonia, decreased glutamine synthetase activity, or both. In the hyperammonemic rat brain, glutamine synthetase is still the only important enzyme for the removal of blood-borne ammonia. Hyperammonemia causes an increase in brain lactate/pyruvate ratios and decreases in brain glutamate and brainstem ATP, consistent with an interference with the malate-aspartate shuttle. In vitro, pathological levels of ammonia also inhibit brain alpha-ketoglutarate dehydrogenase complex and, less strongly, pyruvate dehydrogenase complex. The rat brain does not adapt to prolonged hyperammonemia by increasing its glutamine synthetase activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Ammonia↗

PubMed1998

Ammonia clearance by peritoneal dialysis and continuous arteriovenous hemodiafiltration.

We report the use of continuous arteriovenous hemodiafiltration (CAVHD) in a neonate with severe hyperammonemia due to a urea cycle disorder. We compared the ammonia clearance (C(NH3)) for peritoneal dialysis (PD) and CAVHD. C(NH3) for CAVHD was 7.45 ml/min per m2 at a dialysate flow of 300 ml/h and was 10.55 ml/min per m2 at a dialysate flow rate of 600 ml/h. The mean PD clearance was 2.15 ml/min per m2. Our data suggest that CAVHD is superior to PD for the removal of plasma ammonia. We conclude that CAVHD should be considered a reasonable alternative in the treatment of neonatal hyperammonemia in urea cycle disorders when medical treatment fails.

Ammonia↗

PubMed2005

Improved quality of life and unchanged magnetic resonance brain imaging after living donor liver transplantation for late-onset ornithine transcarbamylase deficiency: report of a case.

We report the case of a 7-year-old girl with ornithine transcarbamylase deficiency whose quality of life (QOL) improved greatly after a living donor liver transplantation (LDLT). Ornithine transcarbamylase deficiency had been diagnosed when she was 2 years old and she finally underwent LDLT, with her father as the donor, when she was 7 years old. The patient had suffered episodes of hyperammonemic encephalopathy ranging from lethargy to coma, treated by hemodialysis twice before LDLT, and her intelligence quotient was borderline for her age. Preoperative magnetic resonance imaging (MRI) showed an atrophic area in the subcortical white matter of the frontal lobe. After LDLT, the patient suffered acute rejection with hyperamylasemia, but not hyperammonemia. Postoperative MRI and quantitative MR spectroscopy showed no changes in the subcortical lesion. She has been followed up carefully for 16 months and has had no further complications or any sign of hyperammonemia.

Atrophy↗

PubMed2002

Progressive liver fibrosis in late-onset argininosuccinate lyase deficiency.

A 4-month-old boy, with late-onset argininosuccinate lyase (ASL) deficiency with hepatomegaly, was treated by protein restricted diet and arginine supplementation; he was followed for 3 years. Hepatomegaly and mild liver dysfunction persisted without significant hyperammonemia. He maintained normal psychomotor development to the age of 12 months, but, at 3 years of age, his developmental status is in the borderline normal range. Liver biopsy performed at 12 months of age demonstrated swollen and pale hepatocytes with abnormal glycogen deposition and mild periportal fibrosis. A subsequent liver biopsy at 3 years of age showed progressive liver fibrosis in the periportal and central areas, which extended into the liver lobule. These findings suggest that liver impairment in ASL deficiency may advance without significant hyperammonemia and underline the importance of repeated liver biopsy in this disorder, even when the plasma ammonia level is well controlled.

Arginine↗

PubMed1991

Ammonium ingestion prevents depletion of hepatic energy metabolites induced by acute ammonium intoxication.

Ingestion of an ammonium containing diet produces hyperammonemia and protects rats against acute ammonium intoxication. Acute ammonium toxicity has been attributed to the depletion of energy metabolite intermediates. We show here that hyperammonemia affords considerable protection against depletion of hepatic energy metabolites evoked by ammonium acetate injection. In control rats there were marked decreases in the content of acetoacetate, beta-hydroxybutyrate, ATP, 2-oxoglutarate, lactate, and pyruvate while phosphoenolpyruvate increased markedly. In hyperammonemic rats beta-hydroxybutyrate, ATP, 2-oxoglutarate, and lactate were not significantly affected while pyruvate increased markedly and phosphoenolpyruvate slightly. These results suggest that in controls the activity of pyruvate kinase is inhibited after ammonium injection while in hyperammonemic rats it is not inhibited. The content of alanine (an inhibitor of pyruvate kinase) reached 2.8 mumol/g in controls and 1.6 mumol/g in hyperammonemic rats, 15 min after ammonium injection. This could explain the different effects of ammonium injection on control and hyperammonemic rats.

Acetates↗

PubMed1987

The potentiation of ammonia toxicity by sodium benzoate is prevented by L-carnitine.

Sodium benzoate has been recommended and even been used for the treatment of hyperammonemia in humans. More recently, a note of caution was raised since it has been shown that in experimental animals, sodium benzoate potentiates ammonia toxicity and inhibits urea synthesis in vitro. This has been further confirmed in the work presented here and the mechanism by which benzoate increases mortality and the levels of blood ammonia in mice given ammonium acetate have also been studied. In hyperammonemia, urea production and N-acetylglutamate levels were decreased by sodium benzoate. Pretreatment of mice with L-carnitine suppressed mortality following ammonium acetate plus sodium benzoate administration. Under these conditions L-carnitine lowered blood ammonia and increased urea production and N-acetylglutamate levels.

Ammonia↗