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Scheiber I.F.,Charles University | Mercer J.F.B.,Deakin University | Dringen R.,University of Bremen | Dringen R.,Center for Environmental Research and Sustainable Technology
Progress in Neurobiology | Year: 2014

Copper is an important trace element that is required for essential enzymes. However, due to its redox activity, copper can also lead to the generation of toxic reactive oxygen species. Therefore, cellular uptake, storage as well as export of copper have to be tightly regulated in order to guarantee sufficient copper supply for the synthesis of copper-containing enzymes but also to prevent copper-induced oxidative stress. In brain, copper is of importance for normal development. In addition, both copper deficiency as well as excess of copper can seriously affect brain functions. Therefore, this organ possesses ample mechanisms to regulate its copper metabolism. In brain, astrocytes are considered as important regulators of copper homeostasis. Impairments of homeostatic mechanisms in brain copper metabolism have been associated with neurodegeneration in human disorders such as Menkes disease, Wilson's disease and Alzheimer's disease. This review article will summarize the biological functions of copper in the brain and will describe the current knowledge on the mechanisms involved in copper transport, storage and export of brain cells. The role of copper in diseases that have been connected with disturbances in brain copper homeostasis will also be discussed. © 2014 Elsevier Ltd. Source


Hirrlinger J.,The Interdisciplinary Center | Dringen R.,University of Bremen | Dringen R.,Center for Environmental Research and Sustainable Technology | Dringen R.,Monash University
Brain Research Reviews | Year: 2010

Astrocytes have important functions in the metabolism of the brain. These cells provide neurons with metabolic substrates for energy production as well as with precursors for neurotransmitter and glutathione synthesis. Both the metabolism of astrocytes and the subsequent supply of metabolites from astrocytes to neurons are strongly affected by alterations in the cellular redox state. The cytosolic redox state of astrocytes depends predominantly on the ratios of the oxidised and reduced partners of the redox pairs NADH/NAD +, NADPH/NADP + and GSH/GSSG. The NADH/NAD + pair is predominately in the oxidised state to accept electrons that are produced during glycolysis. In contrast, the redox pairs NADPH/NADP + and GSH/GSSG are biased towards the reduced state under unstressed conditions to provide electrons for reductive biosyntheses and antioxidative processes, respectively. In this review article we describe the metabolic processes that maintain the redox pairs in their desired redox states in the cytosol of astrocytes and discuss the consequences of alterations of the normal redox state for the regulation of cellular processes and for metabolite trafficking from astrocytes to neurons. © 2009 Elsevier B.V. Source


Tulpule K.,Indian Institute of Science | Dringen R.,University of Bremen | Dringen R.,Center for Environmental Research and Sustainable Technology
Journal of Neurochemistry | Year: 2013

Formaldehyde is an environmental pollutant that is also generated in substantial amounts in the human body during normal metabolism. This aldehyde is a well-established neurotoxin that affects memory, learning, and behavior. In addition, in several pathological conditions, including Alzheimer's disease, an increase in the expression of formaldehyde-generating enzymes and elevated levels of formaldehyde in brain have been reported. This article gives an overview on the current knowledge on the generation and metabolism of formaldehyde in brain cells as well as on formaldehyde-induced alterations in metabolic processes. Brain cells have the potential to generate and to dispose formaldehyde. In culture, both astrocytes and neurons efficiently oxidize formaldehyde to formate which can be exported or further oxidized. Although moderate concentrations of formaldehyde are not acutely toxic for brain cells, exposure to formaldehyde severely affects their metabolism as demonstrated by the formaldehyde-induced acceleration of glycolytic flux and by the rapid multidrug resistance protein 1-mediated export of glutathione from both astrocytes and neurons. These formaldehyde-induced alterations in the metabolism of brain cells may contribute to the impaired cognitive performance observed after formaldehyde exposure and to the neurodegeneration in diseases that are associated with increased formaldehyde levels in brain. The neurotoxin formaldehyde is an environmental pollutant that is also generated during normal brain metabolism. The levels of formaldehyde in brain increase with age and in some neurodegenerative disorders. As excess formaldehyde accelerates glycolysis and glutathione export in neural cells, formaldehyde-induced alterations in brain metabolism and oxidative stress may contribute to the pathological progression of neurodegenerative disorders. The neurotoxin formaldehyde is an environmental pollutant that is also generated during normal brain metabolism. The levels of formaldehyde in brain increase with age and in some neurodegenerative disorders. As excess formaldehyde accelerates glycolysis and glutathione export in neural cells, formaldehyde-induced alterations in brain metabolism and oxidative stress may contribute to the pathological progression of neurodegenerative disorders. © 2013 International Society for Neurochemistry. Source


Tulpule K.,University of Bremen | Tulpule K.,Center for Environmental Research and Sustainable Technology | Dringen R.,University of Bremen | Dringen R.,Center for Environmental Research and Sustainable Technology | Dringen R.,Monash University
Journal of Neurochemistry | Year: 2011

Formaldehyde (Fal) is an environmental neurotoxin that is also endogenously produced in brain. Since the tripeptide glutathione (GSH) plays an important role in detoxification processes in brain cells, we have investigated the consequences of a Fal exposure on the GSH metabolism of brain cells, using astrocyte-rich primary cultures as model system. Treatment of these cultures with Fal resulted in a rapid time- and concentration-dependent depletion of cellular GSH and a matching increase in the extracellular GSH content. Exposure of astrocytes to 1 mm Fal for 3 h did not compromise cell viability but almost completely deprived the cells of GSH. Half-maximal deprivation of cellular GSH was observed after application of 0.3 mm Fal. This effect was rather specific for Fal, since methanol, formate or acetaldehyde did not affect cellular GSH levels. The Fal-stimulated GSH loss from viable astrocytes was completely prevented by semicarbazide-mediated chemical removal of Fal or by the application of MK571, an inhibitor of the multidrug resistance protein 1. These data demonstrate that Fal deprives astrocytes of cellular GSH by a multidrug resistance protein 1-mediated process. © 2011 International Society for Neurochemistry. Source


Bulcke F.,University of Bremen | Bulcke F.,Center for Environmental Research and Sustainable Technology | Thiel K.,Fraunhofer Institute for Manufacturing Engineering and Applied Materials Research | Dringen R.,University of Bremen | Dringen R.,Center for Environmental Research and Sustainable Technology
Nanotoxicology | Year: 2014

To test for consequences of an exposure of brain cells to copper oxide nanoparticles (CuO-NPs), we synthesised and characterised dimercaptosuccinate- coated CuO-NPs. These particles had a diameter of around 5 nm as determined by transmission electron microscopy, while their average hydrodynamic diameter in aqueous dispersion was 136 ± 4 nm. Dispersion in cell-culture medium containing 10% fetal calf serum increased the hydrodynamic diameter to 178 ± 12 nm and shifted the zeta potential of the particles from -49 ± 7 mV (in water) to -10 ± 3 mV. Exposure of cultured primary brain astrocytes to CuO-NPs increased the cellular copper levels and compromised the cell viability in a time-, concentration- and temperature-dependent manner. Application of CuO-NPs in concentrations above 100 μM copper (6.4 μg/ml) severely compromised the viability of the cells, as demonstrated by a lowered 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction capacity, a lowered cellular lactate dehydrogenase activity and an increased membrane permeability for the fluorescent dye propidium iodide. Copper internalisation as well as cell toxicity of astrocytes exposed to CuO-NPs were similar to that observed for cells that had been incubated with copper salts. The CuO-NP-induced toxicity was accompanied by an increase in the generation of reactive oxygen species (ROS) in the cells. Both, ROS formation and cell toxicity in CuO-NP-treated astrocytes, were lowered in the presence of the cell-permeable copper chelator tetrathiomolybdate. These data demonstrate that CuO-NPs are taken up by cultured astrocytes and suggest that excess of internalised CuO-NPs cause cell toxicity by accelerating the formation of ROS. © 2014 Informa UK, Ltd. Source

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