Signaling factors in the mechanism of ammonia neurotoxicity

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 Ca(2+). Such increase in Ca(2+) 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-kappaB). 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.

Two Hypomorphic Alleles of Mouse Ass1 as a New Animal Model of Citrullinemia Type I and Other Hyperammonemic Syndromes

“…43 However, a clear role for oxidative and nitrative stress in CTLN1 has not yet been elucidated. 44 Few reports found increased biomarkers for oxidative stress associated with sustained hypercitrullinemia, 45 or decreased total antioxidant capacity in brain with no changes in antioxidant enzyme activities or MDA formation. 42 In our mouse model, the higher content of MDA-reactive material found in mutant cerebella compared to controls can be linked to either increased oxidative stress, a decreased capacity for glutathione peroxidase/glutathione reductase to catabolyze lipid hydroperoxides, or a combination of both processes.…”

Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

“…Impaired bioenergetics, electrophysiological defects, changes in intracellular pH, altered glutamateric and GABAergic neurotransmission, excitotoxicity, involvement of the peripheral benzodiazepine receptor, 23 oxidative/nitrative stress (ONS) and induction of the mitochondrial permeability transition, have all been identified as major mechanistic events triggered by ammonia. 24,25 Additionally, activation of intracellular signaling systems, including c-fos, 26 mitogen-activated protein kinases, 26 protein kinase G, 27 Src kinase family, 28 ciliary neurotrophic factor, 26 and the transcription factors p53, 29 SP-1 26 and nuclear factor-kappaB (NF-kB) [30][31][32] have all been shown to be involved in the mechanism of ammonia neurotoxicity, particularly in neuroinflammation.…”

Autophagy: Regulation and role in disease

“…The mechanism of ammonia toxicity in the brain has been a matter of debate for years; possible mechanisms that have been proposed include astrocyte swelling, opening of the mitochondrial membrane pore, ROS production, and protein nitration. [389][390][391] Although never previously considered as a possible mechanism for the toxicity of ammonia, compromised autophagy may also contribute. Two facts suggest this hypothesis.…”