Brain hyperammonemia initiates a series of reactions with major consequences: swelling of astrocytes (glial cells) with related communication problems between neurons, and disruption of cerebral metabolism and energy production.
Initially, ammonia is incorporated into glutamate to form glutamine via glutamine …show more content…
Sodium entry is accompanied by water leading to more cell swelling. Additionally, an intracellular Ca2+ overload, together with oxidative stress, activates a set of enzyme capable of producing Nitric Oxide, substance behind astrocytes swelling and destruction of cells structures. NO actions are strictly connected to CNS disorders.
Another effect of toxic ammonia is the inhibition of the key enzyme alpha-ketoglutarate-dehydrogenase -which takes part in the tricarbolxylic acid cycle and is responsible for the oxidative deamination of glutamate to ammonium and ketoglutarate-, with consequential decrement of substrate 2-oxoglutarate availability. The latter is necessary for the Citric acid cycle and ATP production. ATP depletion will make it impossible to control the ion transport across membrane (Na+/K+ membrane pumps).
An excess of ammonia induces metabolic changes: increment of brain levels of lactate, pyruvate, and free glucose, and decrement in brain levels of glycogen and ketone