Hyperammonaemia depresses glucose consumption throughout the brain

Jessy, J; DeJoseph, M. Regina; Hawkins, Richard A.

doi:10.1042/bj2770693

Cited by 40 publications

(14 citation statements)

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“…Nearly identical changes occur when plasma ammonia is increased by artificial means (e.g. by urease injections) in otherwise healthy animals (Jessy et al, 1990(Jessy et al, , 1991.…”

Section: Introductionmentioning

confidence: 90%

“…This decreased rate of energy consumption, reflecting a decrease in the activity of brain cells, is maintained indefinitely thereafter (Hawkins & Mans, 1989a;Jessy et al, 1990;Mans et al, 1990;. The preceding paper (Jessy et al, 1991) showed that the depression in CMRGIc caused by hyperammonaemia correlates more closely with glutamine, a metabolite of ammonia, than with ammonia itself. This was puzzling, because ammonia is thought to be toxic.…”

Section: Introductionmentioning

confidence: 96%

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Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

Hawkins

Jessy

1991

Biochemical Journal

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1. It has been established that chronic hyperammonaemia, whether caused by portacaval shunting or other means, leads to a variety of metabolic changes, including a depression in the cerebral metabolic rate of glucose (CMRGIC), increased permeability of the blood-brain barrier to neutral amino acids, and an increase in the brain content of aromatic amino acids. The preceding paper [Jessy, DeJoseph & Hawkins (1991) Biochem. J. 277, 693-696] showed that the depression in CMRGlC caused by hyperammonaemia correlated more closely with glutamine, a metabolite of ammonia, than with ammonia itself. This suggested that ammonia (NH3 and NH41) was without effect. The present experiments address the question whether ammonia, in the absence of net glutamine synthesis, induces any of the metabolic symptoms of cerebral dysfunction associated with hyperammonaemia. 2. Small doses of methionine sulphoximine, an inhibitor of glutamine synthetase, were used to raise the plasma ammonia levels of normal rats without increasing the brain glutamine content. These hyperammonaemic rats, with plasma and brain ammonia levels equivalent to those known to depress brain function, behaved normally over 48 h. There was no depression of cerebral energy metabolism (i.e. the rate of glucose consumption). Contents of key intermediary metabolites and high-energy phosphates were normal. Neutral amino acid transport (tryptophan and leucine) and the brain contents of aromatic amino acids were unchanged. 3. The data suggest that ammonia is without effect at concentrations less than 1 /tmol/ml if it is not converted into glutamine. The deleterious effect of chronic hyperammonaemia seems to begin with the synthesis of glutamine.

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“…Nearly identical changes occur when plasma ammonia is increased by artificial means (e.g. by urease injections) in otherwise healthy animals (Jessy et al, 1990(Jessy et al, , 1991.…”

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 96%

Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

Hawkins

Jessy

1991

Biochemical Journal

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“…A reduced TCA-cycle rate is consistent with the findings by non-NMR methods that in human CHE the cerebral metabolic rate of oxygen (CMRO 2 ), and cerebral blood flow (CBF) are reduced in parallel with the decline in neurological function (26,32). Furthermore, in porta-caval shunted rats, cerebral glucose metabolism is dramatically reduced in response to hyperammonemia (33,34). However, in in vivo 13 C MR measurements in anesthetized rats under normal and hyperammonemic conditions (35), the TCA-cycle rates were indistinguishable.…”

Section: Abnormalities In Cerebral Metabolism In Chementioning

confidence: 99%

[1‐¹³C] glucose MRS in chronic hepatic encephalopathy in man

Blüml

Moreno-Torres

Ross

2001

Magnetic Resonance in Med

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[1-13 C]-labeled glucose was infused intravenously in a single dose of 0.2 g/kg body weight over 15 min in six patients with chronic hepatic encephalopathy, and three controls. Serial 13 C MR spectra of the brain were acquired. Patients exhibited the following characteristics relative to normal controls: 1) Cerebral glutamine concentration was increased (12.6 ؎ 3.8 vs. 6.5 ؎ 1.9 mmol/kg, P < 0.006) and glutamate was reduced (8.2 ؎ 1.0 vs. 9.9 ؎ 0.6 mmol/kg, P < 0.02). 2)

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“…4 The exact biochemical mechanisms involved in cerebral ammonia toxicity are not fully established, but ammonia-induced alterations in cerebral glucose metabolism may be of importance. 5 In experimental studies of hyperammonemia, both reduced 6,7 and increased 8 cerebral glucose metabolism have been reported. Also, studies of patients with FHF reported both reduced, 9,10 normal, 10 and increased 11 cerebral glucose metabolism, whereas cerebral oxygen metabolism was reduced in all studies.…”

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Cerebral glucose and oxygen metabolism in patients with fulminant hepatic failure

Strauss¹,

Møller²,

Larsen³

et al. 2003

Liver Transplantation

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Hyperammonemia and hyperventilation are consistent findings in patients with fulminant hepatic failure (FHF), which may interfere with cerebral glucose and oxygen metabolism. The aim of the present study is to evaluate whether cerebral oxidative metabolism is preserved early in the course of FHF and whether hyperventilation has an influence on this. We included 16 patients with FHF, 5 patients with cirrhosis of the liver, and 8 healthy subjects. Concomitant blood sampling from an arterial catheter and a catheter in the jugular bulb and measurement of cerebral blood flow by the xenon 133 wash-out technique allowed calculation of cerebral uptake of glucose (CMR gluc ) and oxygen (CMRO 2 ). Both CMR gluc and CMRO 2 were reduced in patients with FHF compared with those with cirrhosis and healthy subjects, i.e., 11.8 ؎ 2.7 v 18.3 ؎ 5.5 and 28.5 ؎ 6.6 mol/100 g/min (P < .05) and 86 ؎ 18 v 164 ؎ 42 and 174 ؎ 27 mol/100 g/min (P < .05). Arteriovenous difference in oxygen and oxygen-glucose index were normal in patients with FHF. Institution of mechanical hyperventilation did not affect glucose and oxygen uptake and hyperventilation did not affect lactatepyruvate ratio or lactate-oxygen index. In conclusion, we found that cerebral glucose and oxygen consumption are proportionally decreased in patients with FHF investigated before clinical signs of cerebral edema. Our data suggest that cerebral oxidative metabolism is retained at this stage of the disease without being compromised by hyperventilation. (Liver Transpl 2003;9:1244-1252.) F ulminant hepatic failure (FHF) is a critical illness with multiorgan failure and hepatic encephalopathy (HE). Cerebral edema and intracranial hypertension are feared and often fatal complications. The pathophysiological background for these complications is not fully understood, but alterations in cerebral metabolism and cerebral blood flow (CBF) seem to be of importance. 1 Metabolism of the brain is different from most other tissues in several aspects. It uses glucose only as an energy source under normal physiological conditions, and in contrast to most other organs, brain cells are permeable to glucose and can use glucose without the intermediation of insulin. 2 However, when necessary, the brain can use other substrates as energy sources, such as ␤-hydroxybutyrate (␤-OHB) and acetoacetate. 3 Hyperammonemia is a consistent finding in FHF, and arterial ammonia concentration seems to correlate with the development of cerebral edema and intracranial hypertension in patients with FHF. 4 The exact biochemical mechanisms involved in cerebral ammonia toxicity are not fully established, but ammonia-induced alterations in cerebral glucose metabolism may be of importance. 5 In experimental studies of hyperammonemia, both reduced 6,7 and increased 8 cerebral glucose metabolism have been reported. Also, studies of patients with FHF reported both reduced, 9,10 normal, 10 and increased 11 cerebral glucose metabolism, whereas cerebral oxygen metabolism was reduced in all studies. [9][10][11][12] The a...

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Hyperammonaemia depresses glucose consumption throughout the brain

Cited by 40 publications

References 12 publications

Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

[1‐¹³C] glucose MRS in chronic hepatic encephalopathy in man

Cerebral glucose and oxygen metabolism in patients with fulminant hepatic failure

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Hyperammonaemia depresses glucose consumption throughout the brain

Cited by 40 publications

References 12 publications

Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

[1‐13C] glucose MRS in chronic hepatic encephalopathy in man

Cerebral glucose and oxygen metabolism in patients with fulminant hepatic failure

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Product

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[1‐¹³C] glucose MRS in chronic hepatic encephalopathy in man