NYMC Faculty Publications
Possible Treatment of End-Stage Hyperammonemic Encephalopathy by Inhibition of Glutamine Synthetase
First Page
119
Last Page
125
Document Type
Article
Publication Date
6-2013
Department
Biochemistry and Molecular Biology
Abstract
Glutamine synthetase (GS) is highly active in astrocytes, and these cells are physiologically and morphologically compromised by hyperammonemia. Hyperammonemia in end-stage acute liver failure (ALF) is often associated with cerebral edema and astrocyte pathology/swelling. Many studies of animal models of hyperammonemia, and, more recently, nuclear magnetic resonance studies of liver disease patients, have shown that cerebral glutamine is elevated in hyperammonemia, contributing to the edema and encephalopathy. The GS inhibitor L-methionine-S,R-sulfoximine (MSO) is protective in animal models against acute ammonia intoxication. MSO is also an inhibitor of glutamate cysteine ligase, is converted to metabolic products, and causes convulsions at high doses. However, the susceptibility to MSO-induced convulsions is species dependent, with primates being relatively resistant. Moreover, it is possible to chronically maintain cerebral GS activity in mice at low levels by MSO treatment without any obvious untoward effects. Furthermore, MSO is protective in a mouse model of ALF. Extreme caution would be needed in administering MSO to patients. Nevertheless, inhibition of brain GS by MSO (or other GS inhibitors) may have therapeutic benefit in ALF.
Recommended Citation
Cooper, A. J. (2013). Possible treatment of end-stage hyperammonemic encephalopathy by inhibition of glutamine synthetase. Metabolic Brain Disease, 28(2), 119-125. doi:10.1007/s11011-012-9338-2
Publisher's Statement
Originally published in Metabolic Brain Disease. https://doi.org/10.1007/s11011-012-9338-2