Effect of glutamine synthetase inhibition on brain and interorgan ammonia metabolism in bile duct ligated rats

Andreas W Fries; Sherry Dadsetan; Susanne Keiding; Lasse Kristoffer Bak; Arne Schousboe; Helle S Waagepetersen; Mette Simonsen; Peter Ott; Hendrik Vilstrup; Michael Sørensen

doi:10.1038/jcbfm.2013.218

Effect of glutamine synthetase inhibition on brain and interorgan ammonia metabolism in bile duct ligated rats

Andreas W Fries, Sherry Dadsetan, Susanne Keiding, Lasse Kristoffer Bak, Arne Schousboe, Helle S Waagepetersen, Mette Simonsen, Peter Ott, Hendrik Vilstrup, Michael Sørensen

13 Citations (Scopus)

Abstract

Ammonia has a key role in the development of hepatic encephalopathy (HE). In the brain, glutamine synthetase (GS) rapidly converts blood-borne ammonia into glutamine which in high concentrations may cause mitochondrial dysfunction and osmolytic brain edema. In astrocyte-neuron cocultures and brains of healthy rats, inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis and increased alanine synthesis. Here, we investigate effects of MSO on brain and interorgan ammonia metabolism in sham and bile duct ligated (BDL) rats. Concentrations of glutamine, glutamate, alanine, and aspartate and incorporation of (15)NH4(+) into these amino acids in brain, liver, muscle, kidney, and plasma were similar in sham and BDL rats treated with saline. Methionine sulfoximine reduced glutamine concentrations in liver, kidney, and plasma but not in brain and muscle; MSO reduced incorporation of (15)NH4(+) into glutamine in all tissues. It did not affect alanine concentrations in any of the tissues but plasma alanine concentration increased; incorporation of (15)NH4(+) into alanine was increased in brain in sham and BDL rats and in kidney in sham rats. It inhibited GS in all tissues examined but only in brain was an increased incorporation of (15)N-ammonia into alanine observed. Liver and kidney were important for metabolizing blood-borne ammonia.

Original language	English
Journal	Journal of Cerebral Blood Flow and Metabolism
Volume	34
Issue number	3
Pages (from-to)	460-6
Number of pages	7
ISSN	0271-678X
DOIs	https://doi.org/10.1038/jcbfm.2013.218
Publication status	Published - Mar 2014

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title = "Effect of glutamine synthetase inhibition on brain and interorgan ammonia metabolism in bile duct ligated rats",

abstract = "Ammonia has a key role in the development of hepatic encephalopathy (HE). In the brain, glutamine synthetase (GS) rapidly converts blood-borne ammonia into glutamine which in high concentrations may cause mitochondrial dysfunction and osmolytic brain edema. In astrocyte-neuron cocultures and brains of healthy rats, inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis and increased alanine synthesis. Here, we investigate effects of MSO on brain and interorgan ammonia metabolism in sham and bile duct ligated (BDL) rats. Concentrations of glutamine, glutamate, alanine, and aspartate and incorporation of (15)NH4(+) into these amino acids in brain, liver, muscle, kidney, and plasma were similar in sham and BDL rats treated with saline. Methionine sulfoximine reduced glutamine concentrations in liver, kidney, and plasma but not in brain and muscle; MSO reduced incorporation of (15)NH4(+) into glutamine in all tissues. It did not affect alanine concentrations in any of the tissues but plasma alanine concentration increased; incorporation of (15)NH4(+) into alanine was increased in brain in sham and BDL rats and in kidney in sham rats. It inhibited GS in all tissues examined but only in brain was an increased incorporation of (15)N-ammonia into alanine observed. Liver and kidney were important for metabolizing blood-borne ammonia.",

author = "Fries, {Andreas W} and Sherry Dadsetan and Susanne Keiding and Bak, {Lasse Kristoffer} and Arne Schousboe and Waagepetersen, {Helle S} and Mette Simonsen and Peter Ott and Hendrik Vilstrup and Michael S{\o}rensen",

year = "2014",

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doi = "10.1038/jcbfm.2013.218",

language = "English",

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pages = "460--6",

journal = "Journal of Cerebral Blood Flow and Metabolism",

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T1 - Effect of glutamine synthetase inhibition on brain and interorgan ammonia metabolism in bile duct ligated rats

AU - Fries, Andreas W

AU - Dadsetan, Sherry

AU - Keiding, Susanne

AU - Bak, Lasse Kristoffer

AU - Schousboe, Arne

AU - Waagepetersen, Helle S

AU - Simonsen, Mette

AU - Ott, Peter

AU - Vilstrup, Hendrik

AU - Sørensen, Michael

PY - 2014/3

Y1 - 2014/3

N2 - Ammonia has a key role in the development of hepatic encephalopathy (HE). In the brain, glutamine synthetase (GS) rapidly converts blood-borne ammonia into glutamine which in high concentrations may cause mitochondrial dysfunction and osmolytic brain edema. In astrocyte-neuron cocultures and brains of healthy rats, inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis and increased alanine synthesis. Here, we investigate effects of MSO on brain and interorgan ammonia metabolism in sham and bile duct ligated (BDL) rats. Concentrations of glutamine, glutamate, alanine, and aspartate and incorporation of (15)NH4(+) into these amino acids in brain, liver, muscle, kidney, and plasma were similar in sham and BDL rats treated with saline. Methionine sulfoximine reduced glutamine concentrations in liver, kidney, and plasma but not in brain and muscle; MSO reduced incorporation of (15)NH4(+) into glutamine in all tissues. It did not affect alanine concentrations in any of the tissues but plasma alanine concentration increased; incorporation of (15)NH4(+) into alanine was increased in brain in sham and BDL rats and in kidney in sham rats. It inhibited GS in all tissues examined but only in brain was an increased incorporation of (15)N-ammonia into alanine observed. Liver and kidney were important for metabolizing blood-borne ammonia.

AB - Ammonia has a key role in the development of hepatic encephalopathy (HE). In the brain, glutamine synthetase (GS) rapidly converts blood-borne ammonia into glutamine which in high concentrations may cause mitochondrial dysfunction and osmolytic brain edema. In astrocyte-neuron cocultures and brains of healthy rats, inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis and increased alanine synthesis. Here, we investigate effects of MSO on brain and interorgan ammonia metabolism in sham and bile duct ligated (BDL) rats. Concentrations of glutamine, glutamate, alanine, and aspartate and incorporation of (15)NH4(+) into these amino acids in brain, liver, muscle, kidney, and plasma were similar in sham and BDL rats treated with saline. Methionine sulfoximine reduced glutamine concentrations in liver, kidney, and plasma but not in brain and muscle; MSO reduced incorporation of (15)NH4(+) into glutamine in all tissues. It did not affect alanine concentrations in any of the tissues but plasma alanine concentration increased; incorporation of (15)NH4(+) into alanine was increased in brain in sham and BDL rats and in kidney in sham rats. It inhibited GS in all tissues examined but only in brain was an increased incorporation of (15)N-ammonia into alanine observed. Liver and kidney were important for metabolizing blood-borne ammonia.

U2 - 10.1038/jcbfm.2013.218

DO - 10.1038/jcbfm.2013.218

M3 - Journal article

C2 - 24346692

SN - 0271-678X

VL - 34

SP - 460

EP - 466

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

IS - 3

ER -

Effect of glutamine synthetase inhibition on brain and interorgan ammonia metabolism in bile duct ligated rats

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