Ammonia toxicity in the central nervous system

Abstract

Ammonia is a regular metabolite in the central nervous system (CNS). However, when it enters the brain from blood in excessive quantities it becomes toxic to CNS cells. Therefore, ammonia is a causative factor in neurological disorders associated with increased blood ammonia, among which hepatic encephalopathy (HE) is a public health problem. Astrocytes are the cells that in the CNS where ammonia is metabolized in a reaction of glutamine synthesis from glutamate and ammonia, and are the primary victim of ammonia toxicity. Bioenergetic failure, oxidative or nitrosative stress and excessive accumulation of glutamine are the interrelated aspects of ammonia-induced astrocytic impairment that contribute to cerebral edema - a major cause of death associated with acute HE. Effects of ammonia on astrocytes radiate to neurons and affect the astrocytic-neuronal interactions. Interference of ammonia with the various steps of the glutamine-glutamate cycle in astrocytes lead to alterations in amino acidergic (glutaminergic and GABAergic) neurotransmission. Ammonia increases GABA-ergic tone by stimulating peripheral benzodiazepine receptors on astrocytes, in this way enhancing the synthesis of neurosteroids that are positive modulators of the GABAA receptors. Direct effects of ammonia on neurons are highlighted by the changes in the NMDA receptor/nitric oxide/cGMP pathway. Overactivation of NMDA receptors in the acute phase of ammonia toxicity is responsible for oxidative and nitrosative stress in neurons (and perhaps in astrocytes), whereas their downregulation upon prolonged exposure to ammonia.leads to impairement of cGMP synthesis held responsible for intellectual and memory deficits of chronic HE patients. Acute hyperammonemia is often associated with increased cerebral blood flow that by a complex mechanism contributes to hyperammonemic brain edema. Ammonia increases the transport across the blood-brain barrier of aromatic amino acids that are precursors of catecholamines: serotonin and dopamine. Ensuing derangements of catecholaminergic transmission are held responsible for sedative effects anfd motor impairment, respectively. Pharmacological interventions to attenuate individual neurotoxic effects of ammonia have in no case reached the stage of clinical trial: slowing the general metabolism with hypothermia is the most recently introduced life-saving paradigm in patients with advanced HE. © 2007 Springer-Verlag US.