Glutamine as a mediator of ammonia neurotoxicity: A critical appraisal

Albrecht, Jan; Norenberg, Michael D.

doi:10.1016/j.bcp.2010.07.024

Cited by 131 publications

(93 citation statements)

References 73 publications

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“…In support of the suggestion that this could have occurred in the neuronal compartment, particularly during acute hyperammonemic conditions, is a study using GABAergic neurons in culture showing prominent removal of 15 NH 4 þ by reductive amination at 3 mM concentrations but not at 0.3 mM. 32 This study by Yudkoff et al 32 showed up to 15% 15 N enrichment of glutamate in neurons, however, studies performed using co-cultures of astrocytes and neurons displayed 50% 15 N enrichment in glutamate after exposure to 5 mM NH 4 þ and up to 45% [ 15 N]glutamate in astrocyte cultures exposed to 1 mM NH 4 þ . 14,33 Hence, it is most likely that the fixation of 15 GDH and synthesis of [ 15 N]alanine primarily occurs in astrocytes.…”

Section: Nhmentioning

confidence: 93%

“…Arterial ammonia concentrations before and 3 hours after treatment with MSO or saline but before the 15 NH 4 þ infusion show that MSO treatment doubled arterial ammonia whereas saline treatment did not ( Figure 4A). After 15 NH 4 þ infusion, the arterial glutamine concentration was decreased in rats pretreated with MSO ( Figure 4B), while that of alanine was unchanged ( Figure 4C).…”

Section: In Vivo Effect Of Mso On Rat Brain Metabolism Of 15 Nh 4 þmentioning

confidence: 97%

“…Cultures were preincubated in the presence or absence (controls) of 10 mM MSO for 1 hour at 371C followed by incubation with NH 4 Cl in the concentrations of either 1 mM, 2.5 mM or 5 mM for 1 hour at 371C. Subsequently, the culture medium was aspirated and the cultures were rinsed twice in phosphate-buffered saline (PBS; 137 mM NaCl, 2.7 mM KCl, 7.3 mM Na 2 HPO 4 , 0.9 mM CaCl 2 , 0.5 mM MgCl 2 , pH 7.4, 371C).…”

Section: Incubation Experiments In Cell Co-culturesmentioning

confidence: 99%

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Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

Dadsetan

Kukolj

Bak

et al. 2013

J Cereb Blood Flow Metab

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Hyperammonemia is a major etiological toxic factor in the development of hepatic encephalopathy. Brain ammonia detoxification occurs primarily in astrocytes by glutamine synthetase (GS), and it has been proposed that elevated glutamine levels during hyperammonemia lead to astrocyte swelling and cerebral edema. However, ammonia may also be detoxified by the concerted action of glutamate dehydrogenase (GDH) and alanine aminotransferase (ALAT) leading to trapping of ammonia in alanine, which in vivo likely leaves the brain. Our aim was to investigate whether the GS inhibitor methionine sulfoximine (MSO) enhances incorporation of 15 NH 4 þ in alanine during acute hyperammonemia. We observed a fourfold increased amount of 15 NH 4 incorporation in brain alanine in rats treated with MSO. Furthermore, co-cultures of neurons and astrocytes exposed to 15 NH 4 Cl in the absence or presence of MSO demonstrated a dose-dependent incorporation of 15 NH 4 into alanine together with increased 15 N incorporation in glutamate. These findings provide evidence that ammonia is detoxified by the concerted action of GDH and ALAT both in vivo and in vitro, a mechanism that is accelerated in the presence of MSO thereby reducing the glutamine level in brain. Thus, GS could be a potential drug target in the treatment of hyperammonemia in patients with hepatic encephalopathy.

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Section: Nhmentioning

confidence: 93%

Section: In Vivo Effect Of Mso On Rat Brain Metabolism Of 15 Nh 4 þmentioning

confidence: 97%

Section: Incubation Experiments In Cell Co-culturesmentioning

confidence: 99%

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Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

Dadsetan

Kukolj

Bak

et al. 2013

J Cereb Blood Flow Metab

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“…Moreover, it has recently been suggested that glutamine induces astrocyte swelling and brain edema through a non-osmotic effect (reviewed by Albrecht et al (Albrecht et al, 2010)). Here, it has been demonstrated, in vitro, that glutamine induces an opening of the mitochondrial transition pore and oxidative stress ( Jayakumar et al, 2004 andZiemińska et al, 2000).…”

Section: Glutamine/glutamatementioning

confidence: 99%

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Bosoi

Rose

2013

Neurochemistry International

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Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that typically develops as a result of acute liver failure or chronic liver disease. Brain edema is a common feature associated with HE. In acute liver failure, brain edema contributes to an increase in intracranial pressure, which can fatally lead to brain stem herniation. In chronic liver disease, intracranial hypertension is rarely observed, even though brain edema may be present. This discrepancy in the development of intracranial hypertension in acute liver failure versus chronic liver disease suggests that brain edema plays a different role in relation to the onset of HE. Furthermore, the pathophysiological mechanisms involved in the development of brain edema in acute liver failure and chronic liver disease are dissimilar. This review explores the types of brain edema, the cells, and pathogenic factors involved in its development, while emphasizing the differences in acute liver failure versus chronic liver disease. The implications of brain edema developing as a neuropathological consequence of HE, or as a cause of HE, are also discussed. HighlightsBrain edema is a common feature in ALF and CLD. HE is inconsistently associated with the presence of brain edema. Fibrous and protoplasmic astrocytes are differentially implicated in the pathogenesis of HE. The pathogenesis of HE is multifactorial causing an array of neurological symptoms.

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“…Ammonia is produced both by bacterial degradation of amines, aminoacids, purines, and urea as well as enterocytic glutaminase activity that converts glutamine to glutamate and ammonia. 6,7 Astrocytes play an important role in the pathogenesis of HE with consequences for neuronal function. Astrocytes have the ability to eliminate ammonia by the synthesis of glutamine through amidation of glutamate by the enzyme glutamine synthetase Hyperammonemia leads to the accumulation of glutamine within astrocytes, which exerts an osmotic stress that causes astrocytes to take in water and swell.…”

mentioning

confidence: 99%

Management of Overt Hepatic Encephalopathy

Sharma

2015

Journal of Clinical and Experimental Hepatology

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Hepatic encephalopathy (HE) is an important complication of cirrhosis with significant morbidity and mortality. Management of HE primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as non-absorbable disaccharides, antimicrobial agents like rifaximin and L-ornithine L-aspartate. The non-absorbable disaccharides which include lactulose and lactitol are considered the first-line therapy for the treatment of HE and in primary and secondary prophylaxis of HE. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Rifaximin is effective in treatment of HE and recent systemic reviews found it comparable to disaccharides and is effective in secondary prophylaxis of HE. H epatic encephalopathy (HE) is a complex neuropsychiatric syndrome, which may complicate acute, chronic liver failure or patients with portal-systemic shunting. It is characterized by changes in mental state including a wide range of neuropsychiatric symptoms ranging from minor signs of altered brain function to deep coma. 1,2 It is one of the commonest indications for admission in intensive care unit in patients with advanced cirrhosis. There were over 40 000 patients hospitalized in the United States alone for a primary diagnosis of HE, resulting in total charges of approximately $932 million. Data in other countries are lacking, hence it causes a huge burden financially to the patient and society. 3 The West Haven Criteria are most often used to grade HE, with scores ranging from I-IV (IV being coma). However, it is a challenge to diagnose patients with minimal hepatic encephalopathy (MHE) or grade 1 HE; so it might be practical to combine these entities and name them covert HE for clinical use and overt HE to patients with grade II to IV. 1,4,5 One of the major tenets of the pathophysiology of HE is hyperammonemia that results from an increased nitrogenous load from the gastrointestinal tract and reduced urea synthesis both due to portal-systemic shunting and decreased urea hepatic synthesis. Brain and skeletal muscle neither remove nor produce ammonium in normal conditions, but they are able to seize ammonium during hyperammonemia, releasing glutamine. Ammonia is produced both by bacterial degradation of amines, aminoacids, purines, and urea as well as enterocytic glutaminase activity that converts glutamine to glutamate and ammonia. 6,7 Astrocytes play an important role in the pathogenesis of HE with consequences for neuronal function. Astrocytes have the ability to eliminate ammonia by the synthesis of glutamine through amidation of glutamate by the enzyme glutamine synthetase Hyperammonemia leads to the accumulation of glutamine within astrocytes, which exerts an osmotic stress that causes astrocytes to take in water and swell. 8,9 This article reviewed the clinical impact, pathogenesis, and management of overt HE in patients with cirrhosis. Articles published between January 1960 and November 2013 were acquired through a MEDLINE search of different combi...

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Glutamine as a mediator of ammonia neurotoxicity: A critical appraisal

Cited by 131 publications

References 73 publications

Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Management of Overt Hepatic Encephalopathy

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