Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity

Abstract

Effects of ammonia on astrocytes play a major role in hepatic encephalopathy, acute liver failure and other diseases caused by increased arterial ammonia concentrations (e.g., inborn errors of metabolism, drug or mushroom poisoning). There is a direct correlation between arterial ammonia concentration, brain ammonia level and disease severity. However, the pathophysiology of hyperammonemic diseases is disputed. One long recognized factor is that increased brain ammonia triggers its own detoxification by glutamine formation from glutamate. This is an astrocytic process due to the selective expression of the glutamine synthetase in astrocytes. A possible deleterious effect of the resulting increase in glutamine concentration has repeatedly been discussed and is supported by improvement of some pathologic effects by GS inhibition. However, this procedure also inhibits a large part of astrocytic energy metabolism and may prevent astrocytes from responding to pathogenic factors. A decrease of the already low glutamate concentration in astrocytes due to increased synthesis of glutamine inhibits the malate-aspartate shuttle and energy metabolism. A more recently described pathogenic factor is the resemblance between NH and K in their effects on the Na,K-ATPase and the Na,K, 2 Cl and water transporter NKCC1. Stimulation of the Na,K-ATPase driven NKCC1 in both astrocytes and endothelial cells is essential for the development of brain edema. Na,K-ATPase stimulation also activates production of endogenous ouabains. This leads to oxidative and nitrosative damage and sensitizes NKCC1. Administration of ouabain antagonists may accordingly have therapeutic potential in hyperammonemic diseases.

Glutamine-Glutamate Cycle Flux Is Similar in Cultured Astrocytes and Brain and Both Glutamate Production and Oxidation Are Mainly Catalyzed by Aspartate Aminotransferase

“…However, these rates are even during hepatic encephalopathy, when they amount to 15 nmol/mL [89], more than one order of magnitude below the flux in the glutamate-glutamine cycle of 500 nmol/g (Figure 1). There is also the big difference that ammonia detoxification under hyperammonemic conditions results in a net increase in glutamine [90,91,92,93], which is at least partly compensated for by glutamine release from brain [94]. In contrast, glutamine formation in astrocytes in the glutamate-glutamine cycle equals glutamine degradation in neurons, providing the possibility that all the ammonia needed for glutamate synthesis in brain might be supplied by ammonia released during conversion of glutamine to glutamate in neurons [6].…”

Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis

“…These toxic effects can lead to secondary mitochondrial failure, and thus, energy deficit. For a complete picture, the reader is referred to the following reviews [38,47,74,75]. Additionally, the similarity between NH 4 + and K + may lead to an increased up-take of ammonium and water, mediated by the Na + /K + -ATPase and NKCC1, a co-transporter of Na + , K + , 2 Cl − , and water, contributing to cerebral edema formation during hyperammonemia [75].…”

“…For a complete picture, the reader is referred to the following reviews [38,47,74,75]. Additionally, the similarity between NH 4 + and K + may lead to an increased up-take of ammonium and water, mediated by the Na + /K + -ATPase and NKCC1, a co-transporter of Na + , K + , 2 Cl − , and water, contributing to cerebral edema formation during hyperammonemia [75]. By impairing astrocyte potassium buffering, hyperammonemia was found to favor depolarization of GABA neurons, leading to the impairment of the cortical inhibitory network and seizures [75,76].…”

“…Additionally, the similarity between NH 4 + and K + may lead to an increased up-take of ammonium and water, mediated by the Na + /K + -ATPase and NKCC1, a co-transporter of Na + , K + , 2 Cl − , and water, contributing to cerebral edema formation during hyperammonemia [75]. By impairing astrocyte potassium buffering, hyperammonemia was found to favor depolarization of GABA neurons, leading to the impairment of the cortical inhibitory network and seizures [75,76]. Histopathologic investigations initially performed on rats with hepatic encephalopathy showed RNA oxidation as a result of elevations in ammonia [41,77].…”

“…Glutamine is a substrate for glutamate and GABA synthesis in glutaminergic and GABAergic neurons, respectively, and therefore, it contributes to the regulation of the glutamine-glutamate-GABA cycle compartmentalized between neurons and astrocytes (Figure 3) [6,71,72,75,82]. This was confirmed by nuclear MRS using 13 C glutamine [71,83,84,85] and by immunochemical studies, where inhibition of GS with MSO increased the level of glutamate in glial cells [11,86].…”