Identifying the direct effects of ammonia on the brain

Elevated concentrations of ammonia in the brain as a result of hyperammonemia leads to cerebral dysfunction involving a spectrum of neuropsychiatric and neurological symptoms (impaired memory, shortened attention span, sleep-wake inversions, brain edema, intracranial hypertension, seizures, ataxia and coma). Many studies have demonstrated ammonia as a major player involved in the neuropathophysiology associated with liver failure and inherited urea cycle enzyme disorders. Ammonia in solution is composed of a gas (NH₃) and an ionic (NH₄ ⁺) component which are both capable of crossing plasma membranes through diffusion, channels and transport mechanisms and as a result have a direct effect on pH. Furthermore, NH₄ ⁺ has similar properties as K⁺ and, therefore, competes with K⁺ on K⁺ transporters and channels resulting in a direct effect on membrane potential. Ammonia is also a product as well as a substrate for many different biochemical reactions and consequently, an increase in brain ammonia accompanies disturbances in cerebral metabolism. These direct effects of elevated ammonia concentrations on the brain will lead to a cascade of secondary effects and encephalopathy.