Ammonia metabolism in the CNS

Kvamme, Elling

doi:10.1016/0301-0082(83)90012-6

Cited by 37 publications

(8 citation statements)

References 186 publications

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“…Although energy failure is often proposed as part of the mechanism for cerebral ammonia toxicity, there is conflict in the literature regarding the actual changes observed in the concentrations of high-energy phosphate compounds during acute hyperammonemia (for review see Kvamme, 1983;Cooper and Plum, 1987). Hawkins et al (1973) reported no changes in ATP or Pi, but a small decrease (-6%) in PCr concentrations in freeze-blown rat brain 5 min after the injection of ammonium acetate.…”

Section: Discussionmentioning

confidence: 99%

Effects of Acute Hyperammonemia on Cerebral Amino Acid Metabolism and pH_i In Vivo, Measured by ¹H and ³¹P Nuclear Magnetic Resonance

Fitzpatrick

Hetherington

Behar

et al. 1989

Journal of Neurochemistry

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The effects of an acute intravenous infusion of ammonium acetate on rat cerebral glutamate and glutamine concentrations, energy metabolism, and intracellular pH were measured in vivo with 1H and 31P nuclear magnetic resonance (NMR). The level of blood ammonia maintained by the infusion protocol used in this study (approximately 500 microM, arterial blood) did not cause significant changes in arterial PCO2, PO2, or pH. Cerebral glutamate levels fell to at least 80% of the preinfusion value, whereas glutamine concentrations increased 170% relative to the preinfusion controls. The fall in brain glutamate concentrations followed a time course similar to that of the rise of brain glutamine. There were no detectable changes in the content of phosphocreatine (PCr) or nucleoside triphosphates (NTP), within the brain regions contributing to the sensitive volume of the surface coil, during the ammonia infusion. Intracellular pH, estimated from the chemical shift of the inorganic phosphate resonance relative to the resonance of PCr in the 31P spectrum, was also unchanged during the period of hyperammonemia. 1H spectra, specifically edited to allow quantitation of the brain lactate content, indicated that lactate rose steadily during the ammonia infusion. Detectable increases in brain lactate levels were observed approximately 10 min after the start of the ammonia infusion and by 50 min of infusion had more than doubled. Spectra acquired from rats that received a control infusion of sodium acetate were not different from the spectra acquired prior to the infusion of either ammonium or sodium acetate.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

Effects of Acute Hyperammonemia on Cerebral Amino Acid Metabolism and pH_i In Vivo, Measured by ¹H and ³¹P Nuclear Magnetic Resonance

Fitzpatrick

Hetherington

Behar

et al. 1989

Journal of Neurochemistry

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“…Ammonia is toxic to the brain. High concentrations of ammonia induce hyperactivity, coma and convulsions prior to death (see Benjamin, 1982;Kvamme, 1983 for discussion). Ammonia neurotoxicity has been implicated in the pathogenesis and/or pathophysiology of a number of diseases including hepatic encephalopathy, Reye's disease, and diseases resulting from the inborn errors of urea metabolism (see Duffy and Plum, 1982 for a detailed discussion).…”

Section: Biochemical Mechanism(s) Underlying the Neurotoxic Effects Omentioning

confidence: 99%

Brain α‐Ketoglutarate Dehydrogenase Complex: Kinetic Properties, Regional Distribution, and Effects of Inhibitors

Lai

Cooper

1986

Journal of Neurochemistry

296

157

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The substrate and cofactor requirements and some kinetic properties of the alpha-ketoglutarate dehydrogenase complex (KGDHC; EC 1.2.4.2, EC 2.3.1.61, and EC 1.6.4.3) in purified rat brain mitochondria were studied. Brain mitochondrial KGDHC showed absolute requirement for alpha-ketoglutarate, CoA and NAD, and only partial requirement for added thiamine pyrophosphate, but no requirement for Mg2+ under the assay conditions employed in this study. The pH optimum was between 7.2 and 7.4, but, at pH values below 7.0 or above 7.8, KGDHC activity decreased markedly. KGDHC activity in various brain regions followed the rank order: cerebral cortex greater than cerebellum greater than or equal to midbrain greater than striatum = hippocampus greater than hypothalamus greater than pons and medulla greater than olfactory bulb. Significant inhibition of brain mitochondrial KGDHC was noted at pathological concentrations of ammonia (0.2-2 mM). However, the purified bovine heart KGDHC and KGDHC activity in isolated rat heart mitochondria were much less sensitive to inhibition. At 5 mM both beta-methylene-D,L-aspartate and D,L-vinylglycine (inhibitors of cerebral glucose oxidation) inhibited the purified heart but not the brain mitochondrial enzyme complex. At approximately 10 microM, calcium slightly stimulated (by 10-15%) the brain mitochondrial KGDHC. At concentrations above 100 microM, calcium (IC50 = 1 mM) inhibited both brain mitochondrial and purified heart KGDHC. The present results suggest that some of the kinetic properties of the rat brain mitochondrial KGDHC differ from those of the purified bovine heart and rat heart mitochondrial enzyme complexes. They also suggest that the inhibition of KGDHC by ammonia and the consequent effect on the citric acid cycle fluxes may be of pathophysiological and/or pathogenetic importance in hyperammonemia and in diseases (e.g., hepatic encephalopathy, inborn errors of urea metabolism, Reye's syndrome) where hyperammonemia is a consistent feature. Brain accumulation of calcium occurs in a number of pathological conditions. Therefore, it is possible that such a calcium accumulation may have a deleterious effect on KGDHC activity.

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“…Furthermore, the enzyme regulates the cerebral concentrations of glutamine and glutamate, which are very important in processes such as ammonia detoxification [4]. A glutamine–glutamate intercellular cycle between neurons and glial cells has been suggested, in such a way that the glutamate released into the synaptic cleft is transported into the glia, converted to glutamine by glutamine synthetase and shifted back to neurons, where PAG will replenish the released glutamate stores.…”

Section: Introductionmentioning

confidence: 99%

The C‐terminus of human glutaminase L mediates association with PDZ domain‐containing proteins¹

et al. 2001

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The enzyme glutaminase in brain is responsible for the synthesis of neurotransmitter glutamate. We used the two-hybrid genetic selection system in yeast to look for interactors of glutaminase in human brain. We have identified two proteins containing PDZ domains, K K1-syntrophin and a glutaminaseinteracting protein, named GIP, that showed association with human glutaminase L, as deduced from specificity test of the two-hybrid system. The complete GIP cDNA clone has 1315 nucleotides with a 372-base open reading frame encoding a 124-amino acids protein. Glutaminase associates with both PDZ proteins through its C-terminal end; mutagenesis of single amino acids revealed the sequence -ESXV as essential for the interaction. These data suggest the possibility that PDZ domain-containing proteins are involved in the regulation of glutaminase in brain. ß

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Ammonia metabolism in the CNS

Cited by 37 publications

References 186 publications

Effects of Acute Hyperammonemia on Cerebral Amino Acid Metabolism and pH_i In Vivo, Measured by ¹H and ³¹P Nuclear Magnetic Resonance

Effects of Acute Hyperammonemia on Cerebral Amino Acid Metabolism and pH_i In Vivo, Measured by ¹H and ³¹P Nuclear Magnetic Resonance

Brain α‐Ketoglutarate Dehydrogenase Complex: Kinetic Properties, Regional Distribution, and Effects of Inhibitors

The C‐terminus of human glutaminase L mediates association with PDZ domain‐containing proteins¹

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Ammonia metabolism in the CNS

Cited by 37 publications

References 186 publications

Effects of Acute Hyperammonemia on Cerebral Amino Acid Metabolism and pHi In Vivo, Measured by 1H and 31P Nuclear Magnetic Resonance

Effects of Acute Hyperammonemia on Cerebral Amino Acid Metabolism and pHi In Vivo, Measured by 1H and 31P Nuclear Magnetic Resonance

Brain α‐Ketoglutarate Dehydrogenase Complex: Kinetic Properties, Regional Distribution, and Effects of Inhibitors

The C‐terminus of human glutaminase L mediates association with PDZ domain‐containing proteins1

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Effects of Acute Hyperammonemia on Cerebral Amino Acid Metabolism and pH_i In Vivo, Measured by ¹H and ³¹P Nuclear Magnetic Resonance

Effects of Acute Hyperammonemia on Cerebral Amino Acid Metabolism and pH_i In Vivo, Measured by ¹H and ³¹P Nuclear Magnetic Resonance

The C‐terminus of human glutaminase L mediates association with PDZ domain‐containing proteins¹