Possible treatment of end-stage hyperammonemic encephalopathy by inhibition of glutamine synthetase.
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.
Department of Biochemistry and Molecular Biology, New York Medical College, 15 Dana Road, Valhalla, NY 10595, USA. arthur_cooper@nymc.edu
Arthur J L
AJ
Cooper
D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors*; D006501:Hepatic Encephalopathy / Q000188:drug therapy*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D022124:Hyperammonemia / Q000188:drug therapy*; D008099:Liver / Q000502:physiology; D008107:Liver Diseases / Q000378:metabolism; D017114:Liver Failure, Acute / Q000188:drug therapy / Q000378:metabolism; D008717:Methionine Sulfoximine / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D008717:Methionine Sulfoximine; D000641:Ammonia; D005974:Glutamate-Ammonia Ligase