Signaling factors in the mechanism of ammonia neurotoxicity
Department of Pathology (D-33), University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101, USA. Metabolic Brain Disease
(Impact Factor: 2.64).
03/2009; 24(1):103-17. DOI: 10.1007/s11011-008-9113-6
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.
Available from: Kevin Curtis
- "The use of such cultures as a model of HE is highly appropriate since substantial evidence invokes a crucial role of ammonia in the pathogenesis of HE, and astrocytes are the principal cells affected in this condition (Norenberg et al. 2009). Moreover, many of the findings occurring in HE in vivo are also observed in ammonia-treated astrocyte cultures, including characteristic morphologic changes, cell swelling, defects in glutamate transport, up-regulation of the 18-kDa translocator protein, reduction in levels of glial fibrillary acidic protein (Sobel et al. 1981; Kretzschmar et al. 1985; Kimura and Budka 1986) and myo-inositol (Norenberg et al. 2009), disturbance in energy metabolism, and evidence of oxidative/nitrative stress (ONS) (Lange et al. 2012). "
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ABSTRACT: Chronic hepatic encephalopathy (CHE) is a major complication in patients with severe liver disease. Elevated blood and brain ammonia levels have been implicated in its pathogenesis, and astrocytes are the principal neural cells involved in this disorder. Since defective synthesis and release of astrocytic factors have been shown to impair synaptic integrity in other neurological conditions, we examined whether thrombospondin-1 (TSP-1), an astrocytic factor involved in the maintenance of synaptic integrity, is also altered in CHE. Cultured astrocytes were exposed to ammonia (NH4Cl, 0.5-2.5 mM) for 1-10 days, and TSP-1 content was measured in cell extracts and culture media. Astrocytes exposed to ammonia exhibited a reduction in intra- and extracellular TSP-1 levels. Exposure of cultured neurons to conditioned media (CM) from ammonia-treated astrocytes showed a decrease in synaptophysin, PSD95 and synaptotagmin levels. CM from TSP-1 overexpressing astrocytes that were treated with ammonia, when added to cultured neurons, reversed the decline in synaptic proteins. Recombinant TSP-1 similarly reversed the decrease in synaptic proteins. Metformin, an agent known to increase TSP-1 synthesis in other cell types also reversed the ammonia-induced TSP-1 reduction. Likewise, we found a significant decline in TSP-1 level in cortical astrocytes, as well as a reduction in synaptophysin content in vivo in a rat model of CHE. These findings suggest that TSP-1 may represent an important therapeutic target for CHE.This article is protected by copyright. All rights reserved.
Available from: Nivin Sharawy
- "Additional proposed mechanism includes ammonia induced activation of mitogen-activated protein kinases and activation of nuclear factor-κb. All of which can lead to enhanced cytokines activity . TNF-α, IL-1β, and IL-6, individually and in combination, induce astrocyte swelling . "
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ABSTRACT: Objective. Encephalopathy and brain edema are serious complications of acute liver injury and may lead to rapid death of patients. The present study was designed to investigate the role of the inflammatory mediators and oxidative stress in the cytotoxic brain oedema and the neuroprotective effects of both minocycline and dexamethasone.
Methods. 48 male albino rats were divided into 4 groups: control group, acute liver injury (ALI) group, minocycline pretreated ALI group, and dexamethasone pretreated ALI group. 24 hours after acute liver injury serum ammonia, liver enzymes, brain levels of heme oxygenase-1 gene, iNOS gene expression, nitrite/nitrate, and cytokines were measured. In addition, the grades of encephalopathy and brain water content were assessed. Results. ALI was associated with significant increases in all measured inflammatory mediators, oxidative stress, iNOS gene expression, and nitrite/nitrate. Both minocycline and dexamethasone significantly modulated the inflammatory changes and the oxidative/nitrosative stress associated with ALI. However, only minocycline but not dexamethasone significantly reduced the cytotoxic brain oedema. Conclusion. Both minocycline and dexamethasone could modulate inflammatory and oxidative changes observed in brain after ALI and could be novel preventative therapy for hepatic encephalopathy episodes.
Available from: Yuen K Ip
- "In mammals, swelling of astrocytes represents the most prominent neuropathological abnormality in acute liver failure , and ammonia has been shown to induce swelling of astrocytes in
, and in
. Aquaporin 4, which acts as a water channel, has been implicated in the swelling process . "
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ABSTRACT: The swamp eel, Monopterus albus, can survive in high concentrations of ammonia (>75 mmol l(-1)) and accumulate ammonia to high concentrations in its brain (∼4.5 µmol g(-1)). Na(+)/K(+)-ATPase (Nka) is an essential transporter in brain cells, and since NH4 (+) can substitute for K(+) to activate Nka, we hypothesized that the brain of M. albus expressed multiple forms of Nka α-subunits, some of which might have high K(+) specificity. Thus, this study aimed to clone and sequence the nka α-subunits from the brain of M. albus, and to determine the effects of ammonia exposure on their mRNA expression and overall protein abundance. The effectiveness of NH4 (+) to activate brain Nka from M. albus and Mus musculus was also examined by comparing their Na(+)/K(+)-ATPase and Na(+)/NH4 (+)-ATPase activities over a range of K(+)/NH4 (+) concentrations. The full length cDNA coding sequences of three nkaα (nkaα1, nkaα3a and nkaα3b) were identified in the brain of M. albus, but nkaα2 expression was undetectable. Exposure to 50 mmol l(-1) NH4Cl for 1 day or 6 days resulted in significant decreases in the mRNA expression of nkaα1, nkaα3a and nkaα3b. The overall Nka protein abundance also decreased significantly after 6 days of ammonia exposure. For M. albus, brain Na(+)/NH4 (+)-ATPase activities were significantly lower than the Na(+)/K(+)-ATPase activities assayed at various NH4 (+)/K(+) concentrations. Furthermore, the effectiveness of NH4 (+) to activate Nka from the brain of M. albus was significantly lower than that from the brain of M. musculus, which is ammonia-sensitive. Hence, the (1) lack of nkaα2 expression, (2) high K(+) specificity of K(+) binding sites of Nkaα1, Nkaα3a and Nkaα3b, and (3) down-regulation of mRNA expression of all three nkaα isoforms and the overall Nka protein abundance in response to ammonia exposure might be some of the contributing factors to the high brain ammonia tolerance in M. albus.
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