Effect of Reducing Brain Glutamine Synthesis on Metabolic Symptoms of Hepatic Encephalopathy

Abstract

Liver failure, or shunting of intestinal blood around the liver, results in hyperammonemia and cerebral dysfunction. Recently it was shown that ammonia caused some of the metabolic signs of hepatic encephalopathy only after it was metabolized by glutamine synthetase in the brain. In the present study, small doses of methionine sulfoximine, an inhibitor of cerebral glutamine synthetase, were given to rats either at the time of portacaval shunting or 3-4 weeks later. The effects on several characteristic cerebral metabolic abnormalities produced by portacaval shunting were measured 1-3 days after injection of the inhibitor. All untreated portacaval-shunted rats had elevated plasma and brain ammonia concentrations, increased brain glutamine and tryptophan content, decreased brain glucose consumption, and increased permeability of the blood-brain barrier to tryptophan. All treated rats had high ammonia concentrations, but the brain glutamine content was normal, indicating inhibition of glutamine synthesis. One day after shunting and methionine sulfoximine administration, glucose consumption, tryptophan transport, and tryptophan brain content remained near control values. In the 3-4-week-shunted rats, which were studied 1-3 days after methionine sulfoximine administration, the effect was less pronounced. Brain glucose consumption and tryptophan content were partially normalized, but tryptophan transport was unaffected. The results agree with our earlier conclusion that glutamine synthesis is an essential step in the development of cerebral metabolic abnormalities in hyperammonemic states.

The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy

“…In agreement with other studies (21,22), portacaval shunting in male Wistar rats resulted in a decrease in liver/body weight ratio to -0.02, indicating liver atrophy. Since the sham-operated rats (AI-NORM group) were pair-fed with the PCS rats (AI-PCS group), possible influences of nutrient deficiencies on the different parameters measured, were equalised.…”

“…It is well known that an increase in brain glutamine and AAA concentrations is already present after 1 day of PCS in rats (21,24), and that the increase is even more pronounced in (sub)acute liver failure with brain glutamine concentrations of 20 to 25 mM (4,17,25,26). The following explanations are available for the rise in brain glutamine concentration after PCS: a) Increased brain glutamine synthesis by glutamine synthase (GS); b) Inhibition of brain glutaminase activity; and c) Decreased glutamine efflux from brain to blood.…”

Brain metabolism of 13N‐ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography†

“…[1][2][3][4] The effects of experimental porta-caval anastomosis with or without pharmacological manipulations of ammonia metabolism have been examined in rat brain, [5][6][7][8][9][10][11][12][13] and the effects of excess ammonia have been tested in astrocyte cell cultures. 14 Human studies of cerebral uptake and metabolism of ammonia included postmortem examinations of brain tissue from patients dying of HE 15 and biochemical analysis of jugular vein blood samples.…”

Brain Glucose Levels in Portacaval-Shunted Rats with Chronic, Moderate Hyperammonemia: Implications for Determination of Local Cerebral Glucose Utilization

“…, <1 J.Lmol/g) and glucose distribution ratios (i.e., <0.2) in portacaval-shunted rats appear, however, to be the exception rather than the rule. In rats shunted by the suture method that have brain ammonia or glutamine levels below �0.7 or 15 J.Lmollg, respec tively, the glucose distribution ratios are near normal and relatively stable for � 12 weeks (Hind felt, 1984;Dejoseph and Hawkins, 199 1;Hawkins et al, 1993) (Tables 3, 5, and 6) suggesting that, at least until very late times after shunting, the brain glucose concentration follows that in plasma, and it should be near-normal as long as the plasma glucose level is maintained. On the other hand, in rats shunted by the glue method, both brain glucose lev els and distribution ratios varied over a very wide range.…”