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PubMed2002

Idiopathic hyperammonemia following an unrelated cord blood transplant for mucopolysaccharidosis I.

Bone marrow transplantation (BMT) has been shown to reverse or stabilize some manifestations of mucopolysaccharidosis I (Hurler syndrome). Idiopathic hyperammonemia (IHA) is a rare complication of solid organ and BMT that is characterized by elevated serum ammonia, normal liver enzymes, and abrupt onset of neurologic deterioration. We present the case of a 14-month-old male patient with Hurler syndrome who developed fatal IHA (ammonia = 2297 micromol/L) 31 days after a cord blood transplant. A complete autopsy was performed, with examination of both frozen and formalin-fixed paraffin-embedded (FFPE) tissues using a variety of special stains and electron microscopy. Hyperammonemia was documented by analysis of antemortem serum and postmortem cerebrospinal and vitreous fluid. Other causes of hyperammonemia, including Reye syndrome, were excluded. Histologic changes included centrilobular microvesicular steatosis of the liver and storage product present in multiple organs. The highly water-soluble mucopolysaccharide (MPS) storage product was best identified by colloidal iron staining of FFPE and unfixed air-dried fresh frozen liver sections. Alcian blue stains failed to convincingly demonstrate MPS in any of the liver sections. This is the first published report, to our knowledge, of IHA in a posttransplant patient younger than 18 years old or following transplantation for Hurler syndrome. Demonstration of the hepatic centrilobular microvesicular steatosis characteristic of IHA was complicated by the diffuse storage of MPS within the liver. MPS storage can be best detected in the liver using colloidal iron staining. Oil-red-O staining may be useful to document microvesicular steatosis in cases with a clinical history of hyperammonemia following solid organ or BMT. Determining if certain subsets of children are at increased risk for IHA requires further study.

Ammonia↗
PubMed2005

Molecular mechanisms of the alterations in NMDA receptor-dependent long-term potentiation in hyperammonemia.

Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission efficacy and is considered the base for some forms of learning and memory. Hyperammonemia impairs LTP in hippocampus. Proper LTP induction in hippocampal slices requires activation of the soluble guanylate cyclase (sGC)-protein kinase G (PKG)-cyclic guanosine monophosphate (cGMP)-degrading phosphodiesterase pathway. Hyperammonemia impairs LTP by impairing the tetanus-induced activation of this pathway. The tetanus induces a rapid cGMP rise, reaching a maximum at 10 s, both in the absence or in the presence of ammonia. The increase in cGMP is followed, in control slices, by a sustained decrease in cGMP because of PKG-mediated activation of cGMP-degrading phosphodiesterase, which is required for maintenance of LTP. Hyperammonemia prevents completely tetanus-induced decrease in cGMP by impairing PKG-mediated activation of cGMP-degrading phosphodiesterase. Addition of 8 Br-cGMP to slices treated with ammonia restores both phosphodiesterase activation and maintenance of LTP. Impairment of LTP in hyperammonemia may be involved in the impairment of the cognitive function in patients with hepatic encephalopathy.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

Chronic hyperammonemia alters motor and neurochemical responses to activation of group I metabotropic glutamate receptors in the nucleus accumbens in rats in vivo.

Hyperammonemia leads to altered cerebral function and neurological alterations in patients with hepatic encephalopathy. We studied the effects of hyperammonemia in rats on the modulation by group I metabotropic glutamate receptors (mGluR) of motor and neurochemical functions in vivo. Locomotion induced by injection of the mGluR agonist DHPG into nucleus accumbens was increased in hyperammonemic rats. In control rats DHPG increased extracellular dopamine (ca. 400%) but not glutamate. In contrast, in hyperammonemic rats DHPG increased extracellular glutamate (ca. 600%), while DHPG-induced dopamine increase was reduced. Blocking mGluR1 receptor with CPCCOEt prevented all DHPG effects, indicating that this receptor mediates its locomotor and neurochemical effects. Hyperammonemic rats showed increased (32%) mGluR1alpha, but not mGluR5 content in nucleus accumbens. These results show that modulation of locomotor and neurochemical functions by mGluRs in nucleus accumbens is strongly altered in hyperammonemia. These alterations may contribute to the neurological alterations in hyperammonemia and liver failure.

Animals↗
PubMed2004

Hyperammonemia impairs long-term potentiation in hippocampus by altering the modulation of cGMP-degrading phosphodiesterase by protein kinase G.

Hyperammonemia impairs long-term potentiation (LTP) in hippocampus, by an unknown mechanism. LTP in hippocampal slices requires activation of the soluble guanylate cyclase (sGC)-protein kinase G (PKG)-cGMP-degrading phosphodiesterase pathway. The aim of this work was to assess whether hyperammonemia impairs LTP by impairing the tetanus-induced activation of this pathway. The tetanus induced a rapid cGMP rise, reaching a maximum at 10 s, both in the absence or presence of ammonia. The increase in cGMP is followed in control slices by a sustained decrease in cGMP due to PKG-mediated activation of cGMP-degrading phosphodiesterase, which is required for maintenance of LTP. Hyperammonemia prevents completely tetanus-induced cGMP decrease by impairing PKG-mediated activation of cGMP-degrading phosphodiesterase. Addition of 8Br-cGMP to slices treated with ammonia restores both phosphodiesterase activation and maintenance of LTP. Impairment of LTP in hyperammonemia may be involved in the impairment of the cognitive function in patients with hepatic encephalopathy.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Sequential activation of soluble guanylate cyclase, protein kinase G and cGMP-degrading phosphodiesterase is necessary for proper induction of long-term potentiation in CA1 of hippocampus. Alterations in hyperammonemia.

Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission efficacy and is considered the base for some forms of learning and memory. Nitric oxide (NO)-induced formation of cGMP is involved in hippocampal LTP. We have studied in hippocampal slices the effects of application of a tetanus to induce LTP on cGMP metabolism and the mechanisms by which cGMP modulates LTP. Tetanus application induced a transient rise in cGMP, reaching a maximum at 10s and decreasing below basal levels 5 min after the tetanus, remaining below basal levels after 60 min. Soluble guanylate cyclase (sGC) activity increased 5 min after tetanus and returned to basal levels at 60 min. The decrease in cGMP was due to sustained tetanus-induced increase in cGMP-degrading phosphodiesterase activity, which remained activated 60 min after tetanus. Tetanus-induced activation of PDE and decrease of cGMP were prevented by inhibiting protein kinase G (PKG). This indicates that the initial increase in cGMP activates PKG that phosphorylates (and activates) cGMP-degrading PDE, which, in turn, degrades cGMP. Inhibition of sGC, of PKG or of cGMP-degrading phosphodiesterase impairs LTP, indicating that proper induction of LTP involves transient activation of sGC and increase in cGMP, followed by activation of cGMP-dependent protein kinase, which, in turn, activates cGMP-degrading phosphodiesterase, resulting in long-lasting reduction of cGMP content. Hyperammonemia is the main responsible for the neurological alterations found in liver disease and hepatic encephalopathy, including impaired intellectual function. Hyperammonemia impairs LTP in hippocampus by altering the modulation of this sGC-PKG-cGMP-degrading PDE pathway. Exposure of hippocampal slices to 1 mM ammonia completely prevents tetanus-induced decrease of cGMP by impairing PKG-mediated activation of cGMP-degrading phosphodiesterase. This impairment is responsible for the loss of the maintenance of LTP in hyperammonemia, and may be also involved in the cognitive impairment in patients with hyperammonemia and hepatic encephalopathy.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Brain regional alterations in the modulation of the glutamate-nitric oxide-cGMP pathway in liver cirrhosis. Role of hyperammonemia and cell types involved.

Hepatic encephalopathy is a complex neuropsychiatric syndrome present in patients with liver disease that includes impaired intellectual function and alterations in personality and neuromuscular coordination. Hyperammonemia and liver failure result in altered glutamatergic neurotransmission, which contributes to hepatic encephalopathy. Alterations in the function of the glutamate-nitric oxide-cGMP pathway may be responsible for some of the neurological alterations found in hepatic encephalopathy. The function of this pathway is altered in brain from patients died with liver cirrhosis and one altered step of the pathway is the activation of soluble guanylate cyclase by nitric oxide, which is increased in cerebral cortex and reduced in cerebellum from these patients. Portacaval anastomosis and bile duct ligation plus hyperammonemia in rats reproduce the alterations in the activation of soluble guanylate cyclase by NO both in cerebellum and cerebral cortex. We assessed whether hyperammonemia is responsible for the region-selective alterations in guanylate cyclase modulation in liver cirrhosis and whether the alteration occurs in neurons or in astrocytes. Activation of guanylate cyclase by nitric oxide is lower in cerebellar neurons exposed to ammonia (1.5-fold) than in control neurons (3.3-fold). The activation of guanylate cyclase by nitric oxide is higher in cortical neurons exposed to ammonia (8.7-fold) than in control neurons (5.5-fold). The activation is not affected in cerebellar or cortical astrocytes. These findings indicate that hyperammonemia is responsible for the differential alterations in the modulation of soluble guanylate cyclase by nitric oxide in cerebellum and cerebral cortex of cirrhotic patients. Moreover, under the conditions used, the alterations occur selectively in neurons and not in astrocytes.

Animals↗
PubMed2006

Hyperammonemia increases sensitivity to LPS.

Metabolic and cognitive alterations occur during hyperammonemia. Here, we report that chronic hyperammonemia also leads to increased sensitivity to LPS. Sparse-fur mice were challenged i.p. with LPS or saline control and then tested for motivation to investigate a novel juvenile over 24 h. Cytokine, ammonia, and urea concentration were quantified at the peak of sickness (2 h post injection). Chronic hyperammonemic Otc(spf-ash) mice displayed more pronounced and prolonged sickness behavior in response to LPS (P=0.02). LPS significantly (P<0.0001) increased plasma concentrations of TNFalpha, IL-1 beta, IL-6, IL-15, IL-9, IL-2, IL-1 alpha, IL-1 beta, Rantes, MIP1 alpha, MIP1 beta, MCP-1, KC, GM-CSF, G-CSF, Eotaxin, IL-13, and IL-12 in both wild type and Otc(spf-ash) mice. No significant genotype/treatment interactions (P>0.1) were detected for any cytokine. Adult Otc(spf-ash) mice (168+/-41 microM) had four times higher plasma ammonia compared to wild type mice (40 +/- 6 microM) (P=0.002). Two hours after LPS injection, plasma ammonia concentrations tended (P=0.08) to decrease in both wild type and Otc(spf-ash) mice. Learning and memory behaviors were assessed in mice under basal conditions to determine the impact of chronic hyperammonemia on cognition. Otc(spf-ash) mice performed significantly poorer in the two trial Y-maze (P=0.02) and the Morris water maze (P=0.001) than their littermate wild type controls. Taken together, these data indicate that chronic hyperammonemia results in impaired cognition and creates a state of LPS hypersensitivity.

Animals↗
PubMed2002

Mitochondrial dysfunction in acute hyperammonemia.

Acute hyperammonemia resulting from congenital urea cycle disorders, Reye syndrome or acute liver failure results in severe neuronal dysfunction, seizures and death. Increasing evidence suggests that acute hyperammonemia results in alterations of mitochondrial and cellular energy function resulting from ammonia-induced inhibition of the tricarboxylic acid cycle enzyme alpha-ketoglutarate dehydrogenase and by activation of the NMDA receptor. Antagonists of this receptor and NOS inhibitors prevent acute ammonia-induced seizures and mortality and prevent acute ammonia-induced changes in mitochondrial calcium homeostasis and cellular energy metabolism. Acute hyperammonemia also results in decreased activities of free radical scavenging enzymes and again, free radical formation due to ammonia exposure is prevented by either NMDA receptor antagonists or NOS inhibitors. Acute hyperammonemia also results in activation of "peripheral-type" benzodiazepine receptors and monoamine oxidase-B, enzymes which are localized on the mitochondrial membranes of astrocytes in the CNS. Activation of these receptors results in mitochondrial swelling and in increased degradation of monoamines, respectively. Alterations of mitochondrial function could contribute to the neuronal dysfunction characteristic of acute hyperammonemic syndromes.

Acute Disease↗
PubMed2002

Hyperammonemia in carnitine-deficient adult JVS mice used by starvation.

Juvenile visceral steatosis (JVS) mouse is an animal model of human primary carnitine deficiency caused by a mutation of the gene encoding carnitine transporter, and suffers from various symptoms, such as fatty liver, growth retardation, hyperammonemia, hypoglycemia, and cardiac hypertrophy. We have shown that hyperammonemia during the weaning period (15-26 days of age) is caused by suppression of urea cycle enzyme gene expression. The suppression resulted from activation of a transcription factor, AP-1. We have found that a cis-element for AP-1 binding is present in the enhancer region of the carbamoylphosphate synthetase (CPS) gene, and that the AP-1 binding site is involved in the suppression of CPS induction by dexamethasone in cultured hepatocytes and in the suppression of CPS expression in the liver of JVS mice. The blood ammonia levels in JVS mice increased during the weaning period, and then decreased to almost control levels after 30 days of age. In this paper, we report that in adult JVS mice, ammonia levels again increased after starvation for at least 24 hr and this effect was suppressed by carnitine treatment. Starvation for 48 hr did not significantly suppress CPS activity in the liver and did not cause any change in hepatic ornithine concentration. The concentration of N-acetylglutamate in the liver of starved JVS mice was not significantly different from that of JVS mice treated with carnitine. These results indicate that the hyperammonemia in carnitine-deficient adult JVS mice during starvation and the suppression by carnitine treatment differ from those found during the weaning period, and thus the cause of hyperammonemia and the mechanism of suppression remain to be solved.

Aging↗
PubMed2005

Chronic hyperammonemia in vivo impairs long-term potentiation in hippocampus by altering activation of cyclic GMP-dependent-protein kinase and of phosphodiesterase 5.

Long-term potentiation (LTP) is impaired in the CA1 area of hippocampal slices from rats with chronic moderate hyperammonemia. We studied the mechanisms by which hyperammonemia in vivo impairs LTP. This process requires sequential activation of soluble guanylate cyclase, cyclic GMP-dependent protein kinase (PKG) and cyclic GMP-degrading phosphodiesterase. Application of the tetanus induced a rapid increase of cyclic GMP in slices from control or hyperammonemic rats, which is followed in control slices by a sustained decrease in cyclic GMP due to sustained activation of cyclic GMP-degrading phosphodiesterase, which in turn is due to sustained activation of PKG. In slices from rats with chronic hyperammonemia tetanus-induced decrease in cyclic GMP was delayed and transient due to lower and transient activation of PKG and of the phosphodiesterase. Hyperammonemia-induced impairment of LTP may be involved in the alterations of cognitive function in patients with hepatic encephalopathy.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Low myo-inositol and high glutamine levels in brain are associated with neuropsychological deterioration after induced hyperammonemia.

The neuropsychological effect of hyperammonemia is variable. This study tests the hypothesis that the effect of ammonia on the neuropsychological function in patients with cirrhosis is determined by the ability of the brain to buffer ammonia-induced increase in glutamine within the astrocyte by losing osmolytes like myo-inositol (mI) and not by the magnitude of the induced hyperammonemia. Fourteen cirrhotic patients with no evidence of overt hepatic encephalopathy were given a 75-g amino acid (aa) solution mimicking the hemoglobin molecule to induce hyperammonemia. Measurement of a battery of neuropsychological function tests including immediate memory, ammonia, aa, and short-echo time proton magnetic resonance spectroscopy were performed before and 4 h after administration of the aa solution. Eight patients showed deterioration in the Immediate Memory Test at 4 h. Demographic factors, severity of liver disease, change in plasma ammonia, and aa profiles after the aa solution were similar in those that showed a deterioration compared with those who did not. In patients who showed deterioration in the memory test, the mI-to-creatine ratio (mI/Cr) was significantly lower at baseline than those that did not deteriorate. In contrast, the glutamate/glutamine-to-Cr ratio was significantly greater in the patients that deteriorated. The observation that deterioration in the memory test scores was greater in those with lower mI/Cr supports the hypothesis that the neuropsychological effects of induced hyperammonemia is determined by the capacity of the brain to handle ammonia-induced increase in glutamine.

Adult↗
PubMed2005

[Hyperammonemia secondary to the use of valproic acid: case report].

Valproic acid has been widely used for the treatment of epilepsy. Although it is usually well tolerated, it has been associated with some side effects. A poor studied side effect is the hyperammonemia, which independs from the drug hepatotoxic action. The hyperammonemia may occurs just after the beginning or during the treatment and is characterized by vomiting, progressive impairment of consciousness, focal neurologic signs and increased seizure frequency. We report boy a 6 year-old boy who presented with hyperammonemia during the use of valproic acid within the therapeutic range. Complementary investigation was negative for aminoacidopathy, organic acidemia and urea cycle disorders. The hypothesis of secondary effect to the valproic acid was reinforced by the normalization of ammonia levels after drug withdrawal. The pathogenesis of valproate-induced hyperammonemia have been discussed. We conclude that routine monitoring of ammonia blood concentration are strongly recommended in patients under valproic acid treatment.

Anticonvulsants↗
PubMed1993

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate receptor during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit.

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate (NMDA) receptor population on brain homogenates in rabbits was studied during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. Homogenates were prepared from brain cortex, hippocampus and striatum. Hepatic encephalopathy was induced by a two-stage liver devascularization procedure and acute hyperammonemia by a prolonged ammonium-acetate infusion; rabbits receiving a sodium-potassium-acetate infusion served as controls. In these animal models extracellular brain glutamate levels are known to be elevated. However no significant alterations in the number nor the affinity of the MK-801 binding sites of the NMDA receptors were found during acute liver failure and acute hyperammonemia. These findings suggest that the NMDA receptor population remains unaltered in experimental encephalopathy from acute liver failure and acute hyperammonemia, despite alterations in extracellular brain glutamate levels.

Acute Disease↗
PubMed1991

Aspartate aminotransferase, malate dehydrogenase, and pyruvate carboxylase activities in rat cerebral synaptic and nonsynaptic mitochondria: effects of 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 activity of the two malate-aspartate shuttle enzymes: aspartate aminotransferase (AAT), malate dehydrogenase (MDH), and on the pyruvate carboxylase (PC) activity were examined in synaptic and nonsynaptic mitochondria from rat brain. With regard to the shuttle enzymes the response to ammonium ions in vitro (3mM NH4Cl) was observed in nonsynaptic mitochondria only, and was manifested by a 27% decrease of AAT activity and a 16% decrease in MDH activity. By contrast, both in vivo conditions primarily affected the synaptic mitochondrial enzymes: TAA-induced HE produced a 26% decrease of synaptic mitochondrial AAT and a 50% decrease of synaptic mitochondrial MDH. Hyperammonemia inhibited synaptic mitochondrial AAT by 30% and synaptic mitochondrial MDH by 45%. HE produced no effect at all in nonsynaptic mitochondria while hyperammonemia produced a 30% increase in the AAT activity, but no changes in MDH. All the experimental conditions affected the nonsynaptic mitochondria PC: ammonium chloride in vitro produced a 20% decrease, TAA-induced HE--a 30% decrease, whereas hyperammonemia inhibited the enzyme by 53%. The PC activity in synaptic mitochondria was very low (about 2% of that measured in nonsynaptic mitochondria), which is consistent with the primarily astrocytic localization of the enzyme.

Ammonia↗
PubMed1993

Effects of experimentally induced hyperammonemia on glial fibrillary acidic protein (GFAP) in the rhombencephalon of goldfish (Carassius auratus L.).

This experimental study was made to know the effect of hyperammonemia on glial fibrillary acidic protein (GFAP) in the glial cells of posterior rhombencephalon in the goldfish (Carassius auratus L.). Hyperammonemia was induced by elevating the ammonia concentration in the tank water to 0.88 mM with ammonium chloride; the ammonia level in the control tank water was < 0.1 mM. The GFAP levels were measured at 8, 16, 30, 60, 90 and 120 days. GFAP was quantified with a digital analysis system and a transient heterogeneous decrease of GFAP was observed. Hyperammonemia mostly affected GFAP in the astrocyte processes associated with cholinergic pathways. An explanation for the adaptive response to hyperammonemia by fish astrocytes is suggested.

Ammonia↗
PubMed1988

Protection against acute hyperammonemia: the role of quaternary amines.

The quaternary amine L-carnitine is able to protect Swiss Albino mice from hyperammonemia when administered in high doses before ammonium acetate. This has been explained by its specific ability to shuttle fatty acids into mitochondria. The structure of L-carnitine resembles the chemical structure of other substances that have been described as being able to protect living cells against osmotic stress. We subjected Swiss Albino mice to hyperammonemia after pretreatment with L-carnitine or "osmoprotectants" such as the quaternary amines choline and betaine, and trimethylamine N-oxide. L-Carnitine proved to be the drug of choice to protect against acute hyperammonemia. Nevertheless, the other tested compounds appeared also to be effective, suggesting that osmoregulation plays a major role in protection against hyperammonemia.

Acetates↗
PubMed1986

Neurologic outcome in premature infants with transient asymptomatic hyperammonemia.

We studied the short-term and long-term effects of transient asymptomatic neonatal hyperammonemia on neurologic function in 21 preterm infants with normal ammonium levels and 25 with hyperammonemia (range 40 to 72 mumol/L) during the first weeks of life. The hyperammonemic infants were prospectively randomized to treatment with orally administered arginine free base 1 to 2 mmol/kg/day for 2 months (n = 13) or to a no-treatment control group (n = 12). Cortical function was assessed by auditory response and habituation during the first month of life. An auditory response was shown by 64% of the hyperammonemic infants and 43% of the normoammonemic infants (P not significant). Plasma ammonium levels at the time of examination bore no consistent relationship to whether an infant responded to an auditory stimulus. Number of trials to reach auditory habituation was also not different, and plasma ammonium level did not correlate with the presence or absence of habituation. IQ testing at 6, 12, 18, and 30 months showed no significant differences between groups. Early plasma ammonium levels did not have an effect on 30-month IQ scores. These findings suggest that transient asymptomatic hyperammonemia in premature infants is not associated with short-term or long-term neurologic deficits through 30 months of age. This study does not support the need for treatment of transient asymptomatic hyperammonemia in the premature infant.

Acoustic Stimulation↗
PubMed2000

Hyperammonemia impairs NMDA receptor-dependent long-term potentiation in the CA1 of rat hippocampus in vitro.

Hyperammonemia is considered the main factor responsible for the neurological and cognitive alterations found in hepatic encephalopathy and in patients with congenital deficiencies of the urea cycle enzymes. The underlying mechanisms remain unclear. Chronic moderate hyperammonemia reduces nitric oxide-induced activation of soluble guanylate cyclase and glutamate-induced formation of cGMP. NMDA receptor-associated transduction pathways, including activation of soluble guanylate cyclase, are involved in the induction of long-term potentiation (LTP), a phenomenon that is considered to be the molecular basis for some forms of memory and learning. Using an animal model we show that chronic hyperammonemia significantly reduces the degree of long-term potentiation induced in the CA1 of hippocampus slices (200% increase in control and 50% increase in slices of hyperammonemic animals). Also, addition of 1 mM ammonia impaired the maintenance of non-decremental LTP. The LTP impairment could be involved in the intellectual impairment present in chronic hepatocerebral disorders associated with hyperammonemia.

2-Amino-5-phosphonovalerate↗