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Possible treatment of end-stage hyperammonemic encephalopathy by inhibition of glutamine synthetase

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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.

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Notes

  1. Ammonia free base (NH3) has a pK a of ~9.2. Thus, under normal intracellular physiological conditions (pH 7.2 – 7.4) ammonia exists predominantly (~99 %) as the conjugate acid, ammonium (NH +4 ). For convenience, ammonia is used throughout the text to indicate the sum of NH3 plus NH +4 .

  2. Commercially available MSO exists as a pair of diastereoisomers (L,S and L,R). The L,S diastereoisomer is a potent GS inhibitor, whereas the L,R diastereoisomer is not (Rowe and Meister 1970). In some studies, as noted in the text, a mixture of D,L-methionine-S,R-sulfoximine isomers was used.

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Acknowledgments

I thank Dr. Saul Brusilow for his help and encouragement and for providing me with some pertinent references regarding the history of MSO. Dr. Brusilow has been a major proponent for the possible use of a GS inhibitor in the treatment of ALF. I also thank Dr. Boris F. Krasnikov for help in construction of the figures. Some of the author’s work mentioned in this review was supported by NIH grant DK 16739.

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No potential conflict of interest relevant to this article is reported.

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  1. Department of Biochemistry and Molecular Biology, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA

    Arthur J. L. Cooper

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Correspondence to Arthur J. L. Cooper.

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Cooper, A.J.L. Possible treatment of end-stage hyperammonemic encephalopathy by inhibition of glutamine synthetase. Metab Brain Dis 28, 119–125 (2013). https://doi.org/10.1007/s11011-012-9338-2

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