Consider what might happen if the plasma ammonia level increases. It is important to take into consideration that ammonia enters the brain rapidly after the plasma ammonia level increases.
Increased formation of glutamine in astrocytes is the major pathway to remove increased ammonia in the brain. It has been demonstrated in OTC patients and in brain tissue of sparse fur (spf) mice, that have a single point mutation in the OTC gene resulting in reduced hepatic OTC activity (~10% of control), that brain glutamine concentration increases 2- to 3-fold. Accordingly, it has been demonstrated in brain cell 3D cultures that the exposure to ammonium chloride increases the intracellular glutamine concentration.
Glutamine is an osmotically active amino acid and is also an important osmolyte in the brain. An increase in intracellular glutamine concentrations will cause cell swelling and brain edema. Water influx is mediated by aquaporins 4 and 9. The increased formation of glutamine also impairs the glutamate-glutamine cycle, depleting glutamate neo-synthesis in astrocytes and neurons. This, in turn, causes a significant loss of the TCA cycle intermediate 2-oxoglutarate which needs to be replaced by the glycolytic breakdown of glucose.
Therefore, hyperammonaemia induces cerebral energy impairment secondary to increased glutamine formation.
