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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.


Scheiber I.F.,University of Bremen | Scheiber I.F.,Center for Environmental Research and Sustainable Technology | Dringen R.,University of Bremen | Dringen R.,Center for Environmental Research and Sustainable Technology
Neurochemistry International | Year: 2013

Copper is an essential element that is required for a variety of important cellular functions. Since not only copper deficiency but also excess of copper can seriously affect cellular functions, the cellular copper metabolism is tightly regulated. In brain, astrocytes appear to play a pivotal role in the copper metabolism. With their strategically important localization between capillary endothelial cells and neuronal structures they are ideally positioned to transport copper from the blood-brain barrier to parenchymal brain cells. Accordingly, astrocytes have the capacity to efficiently take up, store and to export copper. Cultured astrocytes appear to be remarkably resistant against copper-induced toxicity. However, copper exposure can lead to profound alterations in the metabolism of these cells. This article will summarize the current knowledge on the copper metabolism of astrocytes, will describe copper-induced alterations in the glucose and glutathione metabolism of astrocytes and will address the potential role of astrocytes in the copper metabolism of the brain in diseases that have been connected with disturbances in brain copper homeostasis. © 2012 Elsevier Ltd. All rights reserved.


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.


Petters C.,University of Bremen | Petters C.,Center for Environmental Research and Sustainable Technology | Dringen R.,University of Bremen | Dringen R.,Center for Environmental Research and Sustainable Technology
Neurochemistry International | Year: 2015

Magnetic iron oxide nanoparticles (IONPs) are frequently used for biomedical applications. Although nanoparticles can enter the brain, little is known so far on the uptake of IONPs in neurons and on their neurotoxic potential. Hence, we applied dimercaptosuccinate (DMSA)-coated IONPs to cultured primary rat cerebellar granule neurons. These IONPs had average hydrodynamic diameters of around 80-nm and 120-nm when dispersed in incubation medium in the absence and the presence of 10% fetal calf serum, respectively. Acute exposure of neurons with IONPs for up to 6-h did neither alter the cell morphology nor compromise cell viability, although neurons accumulated large amounts of IONPs in a time- and concentration-dependent manner which caused delayed toxicity. For the first 30-min of incubation of neurons at 37-°C with IONPs the cellular iron content increased proportionally to the concentration of IONPs applied irrespective of the absence and the presence of serum. IONP-exposure in the absence of serum generated maximal cellular iron contents of around 3000-nmol iron/mg protein after 4-h of incubation, while the accumulation in the presence of 10% serum was slower and reached already within 1-h maximal values of around 450-nmol iron/mg protein. For both incubation conditions was the increase in cellular iron contents significantly lowered by reducing the incubation temperature to 4-°C. Application of inhibitors of endocytotic pathways did not affect neuronal IONP accumulation in the absence of serum, while inhibitors of clathrin-mediated endocytosis lowered significantly the IONP accumulation in the presence of serum. These data demonstrate that DMSA-coated IONPs are not acutely toxic to cultured neurons and that a protein corona around the particles strongly affects their interaction with neurons. © 2014 Elsevier Ltd. All rights reserved.


Tulpule K.,University of Bremen | Hohnholt M.C.,University of Bremen | Dringen R.,University of Bremen | Dringen R.,Center for Environmental Research and Sustainable Technology
Journal of Neurochemistry | Year: 2013

Formaldehyde is endogenously produced in the human body and brain levels of this compound are elevated in neurodegenerative conditions. Although the toxic potential of an excess of formaldehyde has been studied, little is known on the molecular mechanisms underlying its neurotoxicity as well as on the ability of neurons to metabolize formaldehyde. To address these topics, we have used cerebellar granule neuron cultures as model system. These cultures express mRNAs of various enzymes that are involved in formaldehyde metabolism and were remarkably resistant toward acute formaldehyde toxicity. Cerebellar granule neurons metabolized formaldehyde with a rate of around 200 nmol/(h × mg) which was accompanied by significant increases in the cellular and extracellular concentrations of formate. In addition, formaldehyde application significantly increased glucose consumption, almost doubled the rate of lactate release from viable neurons and strongly accelerated the export of the antioxidant glutathione. The latter process was completely prevented by inhibition of the known glutathione exporter multidrug resistance protein 1. These data indicate that cerebellar granule neurons are capable of metabolizing formaldehyde and that the neuronal glycolysis and glutathione export are severely affected by the presence of formaldehyde. Cultured cerebellar granule neurons efficiently metabolize exogenously applied formaldehyde which results in cellular and extracellular accumulation of formate. Formaldehyde exposure accelerates glycolysis, possibly due to inhibition of cytochrome c oxidase of the mitochondrial respiration chain by cellular formate, and stimulates glutathione (GSH) export via the multidrug resistance protein (Mrp) 1. These alterations could play a role in formaldehyde-induced neurotoxicity. © 2013 International Society for Neurochemistry.


Petters C.,University of Bremen | Petters C.,Center for Environmental Research and Sustainable Technology | Dringen R.,University of Bremen | Dringen R.,Center for Environmental Research and Sustainable Technology
Neurochemical Research | Year: 2014

Astrocyte-rich primary cultures (APCs) are frequently used as a model system for the investigation of properties of brain astrocytes. However, as APCs contain a substantial number of microglial and oligodendroglial cells, biochemical parameters determined for such cultures may at least in part reflect also the presence of the contaminating cell types. To lower the potential contributions of microglial and oligodendroglial cells on properties of the astrocytes in APCs we prepared rat astrocyte-rich secondary cultures (ASCs) by subculturing of APCs and compared these ASCs with APCs regarding basal metabolic parameters, specific enzyme activities and the accumulation of iron oxide nanoparticles. Immunocytochemical characterization revealed that ASCs contained only minute amounts of microglial and oligodendroglial cells. ASCs and APCs did not significantly differ in their specific glucose consumption and lactate production rates, in their specific iron and glutathione contents, in their specific activities of various enzymes involved in glucose and glutathione metabolism nor in their accumulation of iron oxide nanoparticles. Thus, the absence or presence of some contaminating microglial and oligodendroglial cells appears not to substantially modulate the investigated metabolic parameters of astrocyte cultures. © 2013 Springer Science+Business Media New York.


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.


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.


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.


Weinhold M.X.,Center for Environmental Research and Sustainable Technology | Thoming J.,Center for Environmental Research and Sustainable Technology
Carbohydrate Polymers | Year: 2011

Abstract: Chitosan, a natural polyelectrolyte with manyfold applications, is often described as a semi-flexible copolymer with linear chain behavior. Knowledge of the conformation of this polymer is relevant for viscosity-based molecular weight measurements as well as for gelation studies and use as thickener. However, conformational studies reveal a higher variety from compact to relatively stiff chain behavior than expected from the given structure. In this study, we found on the one hand semi-flexible chain behavior and on the other hand dextran-like compact behavior using a size-exclusion chromatography (SEC) system with online triple detection array (refractive index (RI), right and low angle light scattering (RALS, LALS) and viscometry detection). Using different theoretical models different Kuhn segment lengths lK were found for the "semi-flexible" sample: 24 nm using the Benoit-Doty model and Rg-M data, 19 nm using the Odijk-Houwart model and R g-M data as well as 17.5 nm using the Bohdanecký model and [η]-M data. Our results are in accordance with the expected behavior of semi-flexible linear chains from literature. However, the "compact" sample showed values of 9.8 nm in the high molecular weight part with similarity to reports on dextran. © 2011 Elsevier Ltd. All rights reserved.

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