α-Ketoglutaramate: Increased Concentrations in the Cerebrospinal Fluid of Patients in Hepatic Coma

Vergara, Fernando; Plum, Fred; Duffy, Thomas E.

doi:10.1126/science.183.4120.81

Cited by 112 publications

(55 citation statements)

References 21 publications

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“…72 Since a significant fraction of glutamine aminotransferase K, a rate limiting enzyme for alpha-ketoglutaramate production is located within the mitochondria, 73 this interesting finding can likewise be reconciled with the Trojan horse hypothesis. A reconsideration of the potential role of alpha-ketoglutaramate in ammonia neurotoxicity is clearly warranted.…”

Section: The Trojan Horsementioning

confidence: 53%

Glutamine

2006

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Mechanisms involved in hepatic encephalopathy still remain to be defined. Nonetheless, it is well recognized that ammonia is a major factor in its pathogenesis, and that the astrocyte represents a major target of its CNS toxicity. In vivo and in vitro studies have shown that ammonia evokes oxidative/nitrosative stress, mitochondrial abnormalities (the mitochondrial permeability transition, MPT) and astrocyte swelling, a major component of the brain edema associated with fulminant hepatic failure. How ammonia brings about these changes in astrocytes is not well understood. It has long been accepted that the conversion of glutamate to glutamine, catalyzed by glutamine synthetase, a cytoplasmic enzyme largely localized to astrocytes in brain, represented the principal means of cerebral ammonia detoxification. Yet, the "benign" aspect of glutamine synthesis has been questioned. This article highlights evidence that, at elevated levels, glutamine is indeed a noxious agent. We also propose a mechanism by which glutamine executes its toxic effects in astrocytes, the "Trojan horse" hypothesis. Much of the newly synthesized glutamine is subsequently metabolized in mitochondria by phosphate-activated glutaminase, yielding glutamate and ammonia. In this manner, glutamine (the Trojan horse) is transported in excess from the cytoplasm to mitochondria serving as a carrier of ammonia. We propose that it is the glutamine-derived ammonia within mitochondria that interferes with mitochondrial function giving rise to excessive production of free radicals and induction of the MPT, two phenomena known to bring about astrocyte dysfunction, including cell swelling. Future therapeutic approaches might include controlling excessive transport of newly synthesized glutamine to mitochondria and its subsequent hydrolysis. (HEPATOLOGY 2006;44:788-794.)

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Section: The Trojan Horsementioning

confidence: 53%

Glutamine

2006

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“…Increased glutamate concentrations in the cerebrospinal fluid of patients with hepatic encephalopathy suggest that increased extracellular brain glutamate also occurs clinically (Van Sande et al, 1970;Vergara et al, 1974;Watanabe et al, 1984). Increased extracellular glutamate together with a normal NMDA receptor population, might lead to glutamate overexposure.…”

Section: Discussionmentioning

confidence: 99%

“…increased glutamate exposure at the receptor level, during hepatic encephalopathy and hyperammonemia. Increased glutamate concentrations in the cerebrospinal fluid of patients with hepatic encephalopathy suggest that increased glutamate exposure also occurs clinically (Van Sande et al, 1970;Vergara et al, 1974;Watanabe et al, 1984). To explain the paradoxical observation of increased excitatory neurotransmitter molecules in a state of neuroinhibition, the following hypothesis was constructed.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1993

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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.KEYWORDS: hepatic encephalopathy; ammonia; glutamate receptors; NMDAreceptors; MK-801. Abbreviations used in the text: NMDA_N-methyl-D-aspar tate; NH4Ac ammoniumacetate;NaKAc sodium/potassium-acetate; AMPA amino -3 -hydroxy-5 -methylisoxazole-4-propionic acid

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“…It could also explain why metabolites from ammonia metabolism, such as glutamine and alpha-ketoglutaramate, measured in cerebrospinal fluid from patients with HE seem to correlate better with the severity of HE than blood ammonia. 28 The clinical distinction between hyponatremic encephalopathy and hepatic encephalopathy is a challenge. 29 Recent studies have indicated hyponatremia as an independent risk factor for patients with cirrhosis for developing HE.…”

Section: Discussionmentioning

confidence: 99%

Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake

et al. 2013

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Studies have shown decreased cerebral oxygen metabolism (CMRO 2 ) and blood flow (CBF) in patients with cirrhosis with hepatic encephalopathy (HE). It remains unclear, however, whether these disturbances are associated with HE or with cirrhosis itself and how they may relate to arterial blood ammonia concentration and cerebral metabolic rate of blood ammonia (CMRA). We addressed these questions in a paired study design by investigating patients with cirrhosis during and after recovery from an acute episode of HE type C. CMRO 2 , CBF, and CMRA were measured by dynamic positron emission tomography (PET)/computed tomography (CT). Ten patients with cirrhosis were studied during an acute episode of HE; nine were reexamined after recovery. Nine patients with cirrhosis with no history of HE served as controls. Mean CMRO 2 increased from 0.73 lmol oxygen/mL brain tissue/min during HE to 0.91 lmol oxygen/mL brain tissue/min after recovery (paired t test; P < 0.05). Mean CBF increased from 0.28 mL blood/mL brain tissue/min during HE to 0.38 mL blood/mL brain tissue/min after recovery (P < 0.05). After recovery from HE, CMRO 2 and CBF were not significantly different from values in the control patients. Arterial blood ammonia concentration decreased 20% after recovery (P < 0.05) and CMRA was unchanged (P > 0.30); both values were higher than in the control patients (both P < 0.05). Conclusion: The low values of CMRO 2 and CBF observed during HE increased after recovery from HE and were thus associated with HE rather than the liver disease as such. The changes in CMRO 2 and CBF could not be linked to blood ammonia concentration or CMRA. (HEPATOLOGY 2013;57:258-265) B rain energy metabolism is believed to be disturbed in patients with cirrhosis with hepatic encephalopathy (HE).1 Studies have shown decreased cerebral oxygen consumption (CMRO 2 ) and blood flow (CBF) in patients with cirrhosis and HE when compared to patients with cirrhosis without HE or healthy subjects, whereas the latter two groups of subjects had similar values.2-5 Cross-sectional studies point to the reductions being related to the HE condition and not to the liver disease itself. 4,5 In accordance with this, one study reported that reductions in CMRO 2 and CBF were restored when patients, treated with a dopamine agonist, recovered from HE.3 Another study, however, found decreased CMRO 2 but unchanged CBF in patients with a history of HE when compared to patients without a history of HE or healthy controls.6 It thus remains an open question whether the reductions in CMRO 2 and CBF in patients with cirrhosis and HE normalize after recovery from HE, and in the present study we therefore measured CMRO 2 and CBF during and after recovery from an episode of HE in individual patients with cirrhosis.Another key question is how changes in CMRO 2 and CBF may relate to the blood concentration of ammonia. Patients with cirrhosis with HE usually have higher Abbreviations: CBF, cerebral blood flow; CMRA, cerebral metabolic rate of blood ammonia; CMRO 2 , cerebral o...

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α-Ketoglutaramate: Increased Concentrations in the Cerebrospinal Fluid of Patients in Hepatic Coma

Cited by 112 publications

References 21 publications

Glutamine

Glutamine

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

Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake

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