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Signaling factors in the mechanism of ammonia neurotoxicity

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Abstract

Mechanisms involved in hepatic encephalopathy (HE) still remain poorly understood. It is generally accepted that ammonia plays a major role in this disorder, and that astrocytes represent the principal target of ammonia neurotoxicity. In recent years, studies from several laboratories have uncovered a number of factors and pathways that appear to be critically involved in the pathogenesis of this disorder. Foremost is oxidative and nitrosative stress (ONS), which is largely initiated by an ammonia-induced increase in intracellular Ca2+. Such increase in Ca2+ activates a number of enzymes that promote the synthesis of reactive oxygen-nitrogen species, including constitutive nitric oxide synthase, NADPH oxidase and phospholipase A2. ONS subsequently induces the mitochondrial permeability transition, and activates mitogen-activated protein kinases and the transcription factor, nuclear factor-kappaB (NF-κB). These factors act to generate additional reactive oxygen-nitrogen species, to phosphorylate various proteins and transcription factors, and to cause mitochondrial dysfunction. This article reviews the role of these factors in the mechanism of HE and ammonia toxicity with a focus on astrocyte swelling and glutamate uptake, which are important consequences of ammonia neurotoxicity. These pathways and factors provide attractive targets for identifying agents potentially useful in the therapy of HE and other hyperammonemic disorders.

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Acknowledgments

This work was supported by a Merit Review from the Department of Veterans Affairs and by National Institutes of Health Grant DK063311. A.R.J is supported by the American Association for the Study of Liver Disease/American Liver Foundation Grant. We thank Max Norenberg for helpful contributions.

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Authors and Affiliations

  1. Department of Pathology (D-33), University of Miami School of Medicine, P.O. Box 016960, Miami, FL, 33101, USA

    M. D. Norenberg, K. V. Rama Rao & A. R. Jayakumar

  2. Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL, 33101, USA

    M. D. Norenberg

  3. Veterans Affairs Medical Center, Miami, FL, 33101, USA

    M. D. Norenberg

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  1. M. D. Norenberg
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  2. K. V. Rama Rao
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  3. A. R. Jayakumar
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Correspondence to M. D. Norenberg.

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Norenberg, M.D., Rama Rao, K.V. & Jayakumar, A.R. Signaling factors in the mechanism of ammonia neurotoxicity. Metab Brain Dis 24, 103–117 (2009). https://doi.org/10.1007/s11011-008-9113-6

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  • DOI: https://doi.org/10.1007/s11011-008-9113-6

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