Because astrocytes highly express xCT cystine/glutamate antiporter, the micro-environment of CNS in terms of amino acids depends on systemXc-. Glioma-induced edema is the poor prognostic factor. That is why sulfasalazine exhibits the therapeutic effect by attenuating brain edema and inducing ferroptosis (the autophagic cell death by degradation of so amount of ferritin that free form of iron causes excessive ROS.)

A wide spectrum of psychoneurological symptoms has been described and the anatomical substratum is usually associated with brain edema and intracranial hypertension, as well as with changes in the function of brain cells. An increase in blood ammonia, toxic to the brain, depends on the activity of the enzyme glutamine synthetase, the glutamine/glutamate cycle and the brain capacity to eliminate toxic substances. When the concentration of the excitotoxic neurotransmitter glutamate is increased, it acts as a toxic agent, especially when its specific transporters are altered and its uptake is decreased. Glutamine has also been recently considered a toxic substance when its concentration is high, and consequently contributes to brain edema. Finally, the formation of reactive oxygen species, basically produced by mitochondria, influence with their toxic action on membrane lipids, proteins and DNA.

Just the accumulation of ammonia in the brain cannot explain the pathophysiology of   hepatic encephalopathy. Only the impaired urea cycle in the hepatocytes cannot be responsible for the disease.  

Here, I would like to describe the molecular pathophysiology and promising therapeutic strategy for hepatic encephalopathy (HE). This review states that astrocytic glutamine synthetase makes glutamine from glutamate, one of excitotoxic neurotransmitters, and ammonia.1 The source of glutamate in the edematous brain of HE is from the cystine-glutamate antiporter, referred to as system xc−, which exchanges extracellular cystine for intracellular glutamate.2,3 The system xc− is a heterodimeric complex composed of catalytic light chain xCT and regulatory heavy chain 4F2hc, which is crucial for membrane localization of xCT.3 Both damaged oligodendrocytes and activated microglia are responsible for the dysregulated system xc− in HE.3,4 Elevated glutamine release from astrocytes which is promoted by microglia-induced neuroinflammation causes oligodendrocyte excitotoxicity via AMPA receptor activation. That is why NSAIDs have been shown to exhibit partial therapeutic effect. 4 Furthermore, excessive amount of ammonia due to hepatic failure can act as a toxic agent only after the modification with glutamate.1,2 Given that system xc− ameliorates the HE, the development of system xc− inhibitors which can penetrate through BBB should be warranted.

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References

1. Wijdicks EF. Hepatic Encephalopathy. N Engl J Med. 2016;375:1660-1670.

2. Aldridge DR, Tranah EJ, Shawcross DL. Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation. J Clin Exp Hepatol. 2015;5:S7-S20.

3. Bridges RJ, Natale NR, Patel SA. System xc⁻ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol. 2012;165:20-34.

4. Zemtsova I, Görg B, Keitel V, Bidmon HJ, Schrör K, Häussinger D. Microglia activation in hepatic encephalopathy in rats and humans. Hepatology. 2011;54:204-15.