Signaling factors in the mechanism of ammonia neurotoxicity
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.
[Show abstract] [Hide abstract] ABSTRACT: Hyperammonemia induces significant changes in the central nervous system (CNS) in direct association with astroglial functions, such as oxidative damage, glutamatergic excitotoxicity, and impaired glutamine synthetase (GS) activity and pro-inflammatory cytokine release. Classically, lipoic acid (LA) and N-acetylcysteine (NAC) exhibit antioxidant and anti-inflammatory activities by increasing glutathione (GSH) biosynthesis and decreasing pro-inflammatory mediator levels in glial cells. Thus, we evaluated the protective effects of LA and NAC against ammonia cytotoxicity in C6 astroglial cells. Ammonia decreased GSH levels and increased cytokine release and NFκB transcriptional activation. LA and NAC prevented these effects by the modulation of ERK and HO1 pathways. Taken together, these observations show that LA and NAC prevent the ammonia-induced inflammatory response. Copyright © 2015 Elsevier Ltd. All rights reserved.0Comments 2Citations
- "The ERK pathway has been implicated in the regulation of the glial inflammatory response following insult, and is an upstream signal transduction of NFjB (Bobermin et al., 2012; Lee et al., 2010a). Moreover, ERK is involved in the mechanisms of ammonia-induced toxicity (Bobermin et al., 2012Bobermin et al., , 2013 Dai et al., 2013; Norenberg et al., 2009). Here, we observed that the translocation of p65 NFjB into to the nucleus and pro-inflammatory cytokines release levels induced by ammonia were dependent of ERK signaling. "
[Show abstract] [Hide abstract] 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.0Comments 8Citations
- "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). Pathophysiological concentrations of ammonia (0.5, 1.0, and 2.5 mM NH 4 Cl) (Dejong et al. 1993; Singh and Trigun 2010; Carbonero-Aguilar et al. 2011) (also seeTable 1) were added to astrocyte cultures for different time periods (1, 5, and 10 days with regular media changes, once in 2 days for both 5-and 10-day treatment). "
[Show abstract] [Hide abstract] ABSTRACT: Hepatic encephalopathy (HE) represents a nervous system disorder caused due to liver dysfunction. HE is broadly classified as acute/overt and moderate-minimal HE. Since HE syndrome severely affects quality of life of the patients and it may be life threatening, it is important to develop effective therapeutic strategy against HE. Mainly ammonia neurotoxicity is considered accountable for HE. Increased level of ammonia in the brain activates glutamate-NMDA (N-methyl-D-aspartate) receptor (NMDAR) pathway leading to Ca(2+) influx, energy deficit and oxidative stress in the post synaptic neurons. Moreover, NMDAR blockage has been found to be a poor therapeutic option, as this neurotransmitter receptor plays important role in maintaining normal neurophysiology of the brain. Thus, searching new molecular players in HE pathogenesis is of current concern. There is an evolving concept about roles of the trans-membrane channels in the pathogenesis of a number of neurological complications. Pannexin1 (Panx1) is one of them and has been described to be implicated in stroke, epilepsy and ischemia. Importantly, the pathogenesis of these complications relates to some extent with NMDAR over activation. Thus, it is speculated that HE pathogenesis might also involve Panx1. Indeed, some recent observations in the animal models of HE provide support to this argument. Since opening of Panx1 channel is mostly associated with the neuronal dysfunctions, down regulation of this channel could serve as a relevant therapeutic strategy without producing any serious side effects. In the review article an attempt has been made to summarize the current information on implication of Panx1 in the brain disorders and its prospects for being examined as pharmacological target in HE pathogenesis.0Comments 2Citations
- "Since Panx1 activity correlates with neuronal dysfunctions, it may serve as a non-NMDAR pharmacological target against HE and many other neurological disorders associated with NMDAR over activation been found to face serious oxidative stress reflected by reduced glutathione content and significantly increased level of lipid peroxidation (Kosenko et al. 1999). In contrast, chronic and/or low grade HA has been described to induce adaptive changes in the brain biochemistry associated with energy metabolism and oxidative stress (Norenberg et al. 2009). Recently, it has been reported that brain cells activate lactate synthesizing enzymes to adapt against energy depletion during low grade HA exposure (Mehrotra and Trigun 2013). "