Antioxidant and bioenergetic coupling between neurons and astrocytes

Department of Biochemistry and Molecular Biology, Institute of Neurosciences of Castilla y León, University of Salamanca, Salamanca 37007, Spain.
Biochemical Journal (Impact Factor: 4.4). 04/2012; 443(1):3-11. DOI: 10.1042/BJ20111943
Source: PubMed


Oxidative and nitrosative stress underlie the pathogenesis of a broad range of human diseases, in particular neurodegenerative disorders. Within the brain, neurons are the cells most vulnerable to excess reactive oxygen and nitrogen species; their survival relies on the antioxidant protection promoted by neighbouring astrocytes. However, neurons are also intrinsically equipped with a biochemical mechanism that links glucose metabolism to antioxidant defence. Neurons actively metabolize glucose through the pentose phosphate pathway, which maintains the antioxidant glutathione in its reduced state, hence exerting neuroprotection. This process is tightly controlled by a key glycolysis-promoting enzyme and is dependent on an appropriate supply of energy substrates from astrocytes. Thus brain bioenergetic and antioxidant defence is coupled between neurons and astrocytes. A better understanding of the regulation of this intercellular coupling should be important for identifying novel targets for future therapeutic interventions.

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Available from: Angeles Almeida, Apr 04, 2014
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    • "In brain, the astrocytes are considered to play a pivotal role in copper homeostasis [2] [8] [9]. Astrocytes represent one of the main brain cell types which fulfills as partner of neurons many important functions, including control of the extracellular environment [10], supply of metabolic substrates to neurons [11] [12], modulation of synaptic transmission and plasticity [13], and protection of the brain against damage caused by oxidants and toxins [14] [15]. "
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    ABSTRACT: Copper is essential for several important cellular processes, but an excess of copper can also lead to oxidative damage. In brain, astrocytes are considered to play a pivotal role in the copper homeostasis and antioxidative defence. To investigate whether antioxidants and copper chelators can modulate the uptake and the toxicity of copper ions in brain astrocytes, we used primary astrocytes as cell culture model. These cells accumulated substantial amounts of copper during exposure to copper chloride. Copper accumulation was accompanied by a time- and concentration-dependent loss in cell viability, as demonstrated by a lowering in cellular MTT reduction capacity and by an increase in membrane permeability for propidium iodide. During incubations in the presence of the antioxidants ascorbate, trolox or ebselen, the specific cellular copper content and the toxicity in copper chloride-treated astrocyte cultures were strongly increased. In contrast, the presence of the copper chelators bathocuproine disulfonate or tetrathiomolybdate lowered the cellular copper accumulation and the copper-induced as well as the ascorbate-accelerated copper toxicity was fully prevented. These data suggest that predominantly the cellular content of copper determines copper-induced toxicity in brain astrocytes. Copyright © 2015 Elsevier GmbH. All rights reserved.
    Journal of Trace Elements in Medicine and Biology 10/2015; 32:168-76. DOI:10.1016/j.jtemb.2015.07.001 · 2.37 Impact Factor
    • "In case of incident, microglial cells become activated, transform from their resting ramified into their amoeboid form and migrate to the site of interference (Kettenmann et al., 2011; Nayak et al., 2014). Astrocytes cover with their processes most of the brain capillaries which form the BBB (De Bock et al., 2014), supply other brain cell types with nutrients (Bouzier-Sore &Pellerin, 2013; Stobart & Anderson, 2013), are responsible for the homeostasis of ions, water and metals (Dringen et al., 2013; Hohnholt & Dringen, 2013; Verkhratsky et al., 2014) and have important detoxifying functions in brain (Dringen et al., 2015; Fernandez-Fernandez et al., 2012). "
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    ABSTRACT: Iron oxide nanoparticles (IONPs) are used for various biomedical and neurobiological applications. Thus, detailed knowledge on the accumulation and toxic potential of IONPs for the different types of brain cells is highly warranted. Literature data suggest that microglial cells are more vulnerable towards IONP exposure than other types of brain cells. To investigate the mechanisms involved in IONP-induced microglial toxicity, we applied fluorescent dimercaptosuccinate-coated IONPs to primary cultures of microglial cells. Exposure to IONPs for 6 h caused a strong concentration-dependent increase in the microglial iron content which was accompanied by a substantial generation of reactive oxygen species (ROS) and by cell toxicity. In contrast, hardly any ROS staining and no loss in cell viability were observed for cultured primary astrocytes and neurons although these cultures accumulated similar specific amounts of IONPs than microglia. Co-localization studies with lysotracker revealed that after 6 h of incubation in microglial cells, but not in astrocytes and neurons, most IONP fluorescence was localized in lysosomes. ROS formation and toxicity in IONP-treated microglial cultures were prevented by neutralizing lysosomal pH by the application of NH4Cl or Bafilomycin A1 and by the presence of the iron chelator 2,2′-bipyridyl. These data demonstrate that rapid iron liberation from IONPs at acidic pH and iron-catalyzed ROS generation are involved in the IONP-induced toxicity of microglia and suggest that the relative resistance of astrocytes and neurons against acute IONP toxicity is a consequence of a slow mobilization of iron from IONPs in the lysosomal degradation pathway.
    Nanotoxicology 08/2015; DOI:10.3109/17435390.2015.1071445 · 6.41 Impact Factor
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    • "It operates within an important biological network of redox couples comprising NAD þ /NADH, NADP þ /NADPH and GSH/GSSG that work in concert with GSH/ glutathione reductase (GSR), Grx/GSH, Trx/oxidised Trx and thioredoxin reductase (TrxR) and Prx to maintain redox homeostasis (see Fig. 1). In neurons, oxidation of glucose via the pentose phosphate pathway provides the NADPH needed by GSR to regenerate GSH from GSSG [7]. Moreover, neurons preferentially oxidise glucose for antioxidant defence rather than energy production , due to low activity of the key activator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 [8]. "
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    ABSTRACT: This review provides an overview of the biochemistry of thiol redox couples and the significance of thiol redox homeostasis in neurodegenerative disease. The discussion is centred on cysteine/cystine redox balance, the significance of the xc(-) cystine-glutamate exchanger and the association between protein thiol redox balance and neurodegeneration, with particular reference to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. The role of thiol disulphide oxidoreductases in providing neuroprotection is also discussed. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
    04/2015; 5:186-194. DOI:10.1016/j.redox.2015.04.004
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