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

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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 NH4 + 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.

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  1. Laboratory of Metabolic Brain Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, People’s Republic of China

    Leif Hertz, Dan Song & Liang Peng

  2. Henry M. Jackson Foundation, 6720-A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA

    Ye Chen

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Hertz, L., Song, D., Peng, L. et al. Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity. Neurochem Res 42, 721–736 (2017). https://doi.org/10.1007/s11064-016-1966-1

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