Energy metabolism in brain cells: effects of elevated ammonia concentrations

Both neurons and astrocytes have high rates of glucose utilization and oxidative metabolism. Fully 20% of glucose consumption is used for astrocytic production of glutamate and glutamine, which during intense glutamatergic activity leads to an increase in glutamate content, but at steady state is compensated for by an equally intense oxidation of glutamate. The amounts of ammonia used for glutamine synthesis and liberated during glutamine hydrolysis are large, compared to the additional demand for glutamine synthesis in hyperammonemic animals and patients with hepatic encephalopathy. Nevertheless, elevated ammonia concentrations lead to an increased astrocytic glutamine production and an elevated content of glutamine combined with a decrease in glutamate content, probably mainly in a cytosolic pool needed for normal activity of the malate-asparate shuttle (MAS); another compartment generated by glutamine hydrolysis is increased. As a result of reduced MAS activity the pyruvate/lactate ratio is decreased in astrocytes but not in neurons and decarboxylation of pyruvate to form acetyl coenzyme A is reduced. Elevated ammonia concentrations also inhibit decarboxylation of α-ketoglutarate in the TCA cycle. This effect occurs in both neurons and astrocytes, is unrelated to MAS activity and seen after chronic treatment with ammonia even in the absence of elevated ammonia concentrations.