Open AccessAcute Liver Failure in Rats Activates Glutamine-Glutamate Cycle but Declines Antioxidant Enzymes to Induce Oxidative Stress in Cerebral Cortex and Cerebellum
Author(s) -
Santosh Singh,
Papia Mondal,
Surendra Kumar Trigun
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0095855
Subject(s) - glutamine synthetase , hyperammonemia , oxidative stress , glutamine , antioxidant , hepatic encephalopathy , glutamate receptor , excitotoxicity , thioacetamide , medicine , glutaminase , cerebellum , endocrinology , cerebral cortex , lipid peroxidation , biochemistry , chemistry , biology , amino acid , cirrhosis , receptor
Background and Purpose Liver dysfunction led hyperammonemia (HA) causes a nervous system disorder; hepatic encephalopathy (HE). In the brain, ammonia induced glutamate-excitotoxicity and oxidative stress are considered to play important roles in the pathogenesis of HE. The brain ammonia metabolism and antioxidant enzymes constitute the main components of this mechanism; however, need to be defined in a suitable animal model. This study was aimed to examine this aspect in the rats with acute liver failure (ALF). Methods ALF in the rats was induced by intraperitoneal administration of 300 mg thioacetamide/Kg. b.w up to 2 days. Glutamine synthetase (GS) and glutaminase (GA), the two brain ammonia metabolizing enzymes vis a vis ammonia and glutamate levels and profiles of all the antioxidant enzymes vis a vis oxidative stress markers were measured in the cerebral cortex and cerebellum of the control and the ALF rats. Results The ALF rats showed significantly increased levels of ammonia in the blood (HA) but little changes in the cortex and cerebellum. This was consistent with the activation of the GS-GA cycle and static levels of glutamate in these brain regions. However, significantly increased levels of lipid peroxidation and protein carbonyl contents were consistent with the reduced levels of all the antioxidant enzymes in both the brain regions of these ALF rats. Conclusion ALF activates the GS-GA cycle to metabolize excess ammonia and thereby, maintains static levels of ammonia and glutamate in the cerebral cortex and cerebellum. Moreover, ALF induces oxidative stress by reducing the levels of all the antioxidant enzymes which is likely to play important role, independent of glutamate levels, in the pathogenesis of acute HE.