11 results on '"Dringen R"'
Search Results
2. 1.3 Pentose Phosphate Pathway and NADPH Metabolism.
- Author
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Dringen, R., Hoepken, H. H., Minich, T., and Ruedig, C.
- Abstract
The pentose phosphate pathway (PPP) is an essential metabolic pathway in the glucose metabolism of the brain. Under normal conditions, the PPP plays a minor part in total glucose consumption. However, its products NADPH and ribose-5-phosphate have important functions in brain cells as electron donor for various enzymatic reactions and as precursor for the synthesis of nucleotides, respectively. This chapter discusses properties of PPP enzymes and the regulation of the flux of metabolites through the PPP in brain and neural cells. The functions of the PPP in neural cells are described with special emphasis on the roles of cytosolic NADPH in brain cells. This reduced cofactor is highly important for the antioxidative defense of brain cells by glutathione (GSH) redox cycling. In addition, NADPH provides reduction equivalents for biosynthetic reactions as well as for the generation of nitric oxide and superoxide. Finally, evidence for a connection between human diseases and alterations in the activities of PPP enzymes in brain are presented. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
3. Glutathione peroxidase-1 contributes to the protection of glutamine synthetase in astrocytes during oxidative stress.
- Author
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Knorpp, T., Robinson, S. R., Crack, P. J., and Dringen, R.
- Subjects
GLUTATHIONE ,GLUTAMINE synthetase ,ASTROCYTES ,OXIDATIVE stress ,XANTHINE oxidase - Abstract
Glutamine synthetase (GS) is an astrocytic enzyme that is essential for the glutamate–glutamine cycle between neurons and astrocytes. To measure the effects of oxidative stress on the activity of GS in astrocytes, astrocyte-rich primary cultures from the brains of wild-type and glutathione peroxidase-1 deficient mice (GPx1(−/−)) were exposed to a chronic hydrogen peroxide-generating system consisting of xanthine oxidase, hypoxanthine and superoxide dismutase. The specific activity of GS was strongly diminished by chronic exposure to hydrogen peroxide in astrocytes cultured from both mouse lines. After 60 min of oxidative stress in the presence of 5 mU/mL, 10 mU/mL and 20 mU/mL of xanthine oxidase, the specific GS activity of wild-type astrocytes was reduced to 47%, 22% and 13% of the initial activity, respectively. For all activities of xanthine oxidase applied, astrocytes from GPx1(−/−) mice experienced a significantly greater rate of GS inactivation compared to their wild-type counterparts. These results confirm that GS is sensitive to inactivation by chronic peroxide stress in viable astrocytes and show that glutathione peroxidase-1 helps to protect GS from inactivation by oxidative stress. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
4. Identification of Nℇ-(carboxymethyl)lysine-positive cells in astroglia-rich primary cultures.
- Author
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Pawlowski, P. G. and Dringen, R.
- Subjects
BRAIN ,CELLS ,PROTEINS ,AMINO acids ,NEUROGLIA ,BASIC proteins ,LABORATORY rats - Abstract
Summary. Astroglia-rich primary cultures from rat brain were used to investigate the presence in glial cells of N
ℇ -(carboxymethyl)lysine (CML), an advanced glycation endproduct. Westernblot analysis of homogenates of rat brain as well as of astroglia-rich cultures demonstrated the presence of CML-modified proteins in these samples. Immunocytochemical staining of astroglia-rich cultures revealed that only a minority of the cells in these cultures were intensively stained for CML. The staining intensity of CML-positive cells was strongly reduced, if the cells were not permeabilized, indicating that intracellular proteins were CML-modified. The CML-positive cells were identified as astrocytes and oligodendrocytes by double-labelling immunocytochemical staining for CML and the cellular markers galactocerobroside, myelin basic protein and glial fibrillary acidic protein. In contrast to other glial cells, microglial cells in astroglia-rich cultures were CML-negative. The finding that only a minority of cells in astroglia-rich cultures contains high amounts of intracellular CML-modified proteins indicates that specific properties of these CML-positive cells are responsible for the CML-formation in these cells. [ABSTRACT FROM AUTHOR]- Published
- 2003
- Full Text
- View/download PDF
5. Oligodendroglial cells in culture effectively dispose of exogenous hydrogen peroxide: comparison with cultured neurones, astroglial and microglial cells.
- Author
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Hirrlinger, J., Resch, A., Gutterer, J.M., and Dringen, R.
- Subjects
OLIGODENDROGLIA ,HYDROGEN peroxide ,ANTIOXIDANTS - Abstract
To investigate the antioxidative capacities of oligodendrocytes, rat brain cultures enriched for oligodendroglial cells were prepared and characterized. These cultures contained predominantly oligodendroglial cells as determined by immunocytochemical staining for the markers galactocerebroside and myelin basic protein. If oligodendroglial cultures were exposed to exogenous hydrogen peroxide (100 µM), the peroxide disappeared from the incubation medium following first order kinetics with a half-time of approximately 18 min. Normalization of the disposal rate to the protein content of the cultures by calculation of the specific hydrogen peroxide detoxification rate constant revealed that the cells in oligodendroglial cultures have a 60% to 120% higher specific capacity to dispose of hydrogen peroxide than cultures enriched for astroglial cells, microglial cells or neurones. Oligodendroglial cultures contained specific activities of 133.5 ± 30.4 nmol × min[sup -1] × mg protein[sup -1] and 27.5 ± 5.4 nmol × min[sup -1] × mg protein[sup -1] of glutathione peroxidase and glutathione reductase, respectively. The specific rate constant of catalase in these cultures was 1.61 ± 0.54 min[sup -1] × mg protein[sup -1]. Comparison with data obtained by identical methods for cultures of astroglial cells, microglial cells and neurones revealed that all three of the enzymes which are involved in hydrogen peroxide disposal were present in oligodendroglial cultures in the highest specific activities. These results demonstrate that oligodendroglial cells in culture have a prominent machinery for the disposal of hydrogen peroxide, which is likely to support the protection of these cells in brain against peroxides when produced by these or by surrounding brain cells. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
6. Effects of dopamine on the glutathione metabolism of cultured astroglial cells: implications for Parkinson's disease.
- Author
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Hirrlinger, J., Schulz, J.B., and Dringen, R.
- Subjects
DOPAMINE ,GLUTATHIONE ,PARKINSON'S disease - Abstract
To investigate the effects of dopamine (DA) on the release of glutathione (GSH) from astrocytes, we used astroglia-rich primary cultures from the brains of newborn rats. In the absence of DA, GSH accumulated in the medium of these cultures with a constant rate. In contrast, during incubation of the cells with 50 µM DA extracellular GSH was not detectable anymore. This disappearance of extracellular GSH was prevented by superoxide dismutase, indicating that DA does not affect GSH release but rather reacts with the released GSH in a superoxide-dependent reaction. Incubation of astroglial cultures with 0.5 and 1 mM DA established almost constant extracellular concentrations of H[sub 2]O[sub 2] of 5 µM and 15 µM, respectively. Under these conditions astroglial cultures release glutathione disulphide (GSSG). This GSSG export was blocked by catalase and by MK571, an inhibitor of the multidrug resistance protein 1. The effects of DA on the extracellular accumulations of GSH and GSSG were not modulated by inhibitors of DA receptors, DA transport, and monoamine oxidases. The other catecholamines adrenaline and noradrenaline showed similar effects on the accumulation of GSH and GSSG in the medium compared with those obtained for DA. In conclusion, the data presented demonstrate that DA affects astroglial GSH metabolism by two mechanisms: (i) directly by chemical reaction with extracellular GSH, and (ii) indirectly by generation of hydrogen peroxide that leads to the efflux of GSSG from astroglial cells. These observations are discussed in the context of the brain's GSH metabolism in Parkinson's disease. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
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7. Expression of mRNAs of multidrug resistance proteins (Mrps) in cultured rat astrocytes, oligodendrocytes, microglial cells and neurones.
- Author
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Hirrlinger, J., König, J., and Dringen, R.
- Subjects
MULTIDRUG resistance ,MESSENGER RNA - Abstract
Multidrug resistance proteins (Mrps) are ATP-driven export pumps that mediate the export of organic anions from cells. So far only little information is available on expression and physiological functions of Mrps in brain. The expression of mRNAs of six Mrp paralogs in rat brain, as well as in rat cultures enriched for neurones, astrocytes, oligodendrocytes and microglial cells, was studied by qualitative and semiquantitative RT-PCR analysis. In adult rat brain as well as in neural cell cultures the mRNAs coding for Mrp1, Mrp3, Mrp4 and Mrp5 were detected. Semiquantitative analysis revealed that the mRNAs coding for Mrp1 and Mrp5 were more abundant in the four cell culture types than mRNAs of the other Mrps. mRNAs coding for Mrp3 and Mrp4 were found at significant levels in cultured astrocytes and microglial cells, whereas cultures of neurones and oligodendrocytes contained only marginal quantities of these mRNAs. Putative physiological functions of Mrps in brain cells are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
8. Increased hippocampal DNA oxidation in serotonin transporter deficient mice.
- Author
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Mössner, R., Dringen, R., Persico, A. M., Janetzky, B., Okladnova, O., Albert, D., Götz, M., Benninghoff, J., Schmitt, A., Gerlach, M., Riederer, P., and Lesch, K. P.
- Subjects
SEROTONIN ,GLUTATHIONE transferase ,DNA ,OXIDATION ,NEURAL transmission ,LABORATORY mice - Abstract
Summary. The serotonin transporter (5HTT) is the molecule responsible for the high-affinity reuptake of 5HT from the synaptic cleft. Mice lacking the 5HTT exhibit highly elevated extracellular concentrations of 5HT. We assessed whether the glutathione detoxification system is altered in 5HTT-deficient mice. While levels of reduced and oxidized glutathione were unchanged, glutathione metabolising enzymes showed a differential pattern of modulation. Glutathione peroxidase was reduced in frontal cortex, brainstem, and cerebellum of 5HTT-deficient mice, though not to a statistically significant extent, while a putative isoform of the detoxifying enzyme glutathione-S-transferase pi was decreased in a number of brain regions, especially in brainstem. At the level of the DNA, we found an increase of oxidative DNA adducts in the hippocampus of 5HTT-deficient mice. Given the importance of the hippocampus in learning and memory, this may be the most important neurochemical consequence of the absence of the 5HTT. [ABSTRACT FROM AUTHOR]
- Published
- 2002
9. The multidrug resistance protein MRP1 mediates the release of glutathione disulfide from rat astrocytes during oxidative stress.
- Author
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Hirrlinger, J., König, J., Keppler, D., Lindenau, J., Schulz, J.B., and Dringen, R.
- Subjects
PROTEINS ,MULTIDRUG resistance ,GLUTATHIONE - Abstract
The release of glutathione disulfide has been considered an important process for the maintenance of a reduced thiol redox potential in cells during oxidative stress. In cultured rat astrocytes, permanent hydrogen peroxide-induced oxidative stress caused a rapid increase in intracellular glutathione disulfide, which was followed by the appearance of glutathione disulfide in the medium. Under these conditions, the viability of the cells was not compromised. In the presence of cyclosporin A and the quinoline-derivative MK571, inhibitors of multidrug resistance proteins (MRP1 and MRP2), glutathione disulfide accumulated in cells and the release of glutathione disulfide from astrocytes during H[sub 2]O[sub 2] stress was potently inhibited, suggesting a contribution of MRP1 or MRP2 in the release of glutathione disulfide from astrocytes. Using RT-PCR we amplified a cDNA from astroglial RNA with a high degree of homology to MRP1 from humans and mouse. In contrast, no fragment was amplified by using primers specific for rat MRP2. In addition, the presence of MRP1 protein in astrocytes was demonstrated by its immunolocalization in cells expressing the astroglial marker protein glial fibrillary acidic protein. Our data identify rat astrocytes as a MRP1-expressing brain cell type and demonstrate that this transporter participates in the release of glutathione disulfide from astrocytes during oxidative stress. [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
- View/download PDF
10. Astroglial glutathione export and the supply of glutathione precursors to neurons.
- Author
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Dringen, R. and Hirrlinger, J.
- Subjects
NEURONS ,GLUTATHIONE ,BRAIN - Abstract
Neurons rely on the availability of extracellular cysteine for their glutathione (GSH) synthesis. This amino acid is generated by processing of extracellular GSH. Astrocytes play an important role in the GSH metabolism of the brain, since of the different brain cell type investigated only astrocytes release substantial amounts of GSH. The multidrug resistance protein 1 (Mrp1) which is expressed in astrocytes in vitro and in vivo mediates about 60% of the GSH release from cultured astrocytes. Extracellular GSH serves as substrate for the astroglial ectoenzyme gamma-glutamyl transpeptidase (gGT). Inhibition of this enzyme prevents the astroglia-mediated increase in the GSH level of cocultured neurons. The dipeptide CysGly, which is produced by gGT, is hydrolysed by the neuronal aminopeptidase N to glycine and cysteine. By providing the glutamate-precursor glutamine and the dipeptide CysGly astrocytes supply to neurons precursors for all three amino acids which are required for neuronal GSH synthesis. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
11. ADVANCED GLYCATION ENDPRODUCTS INCREASE β-AMYLOID TOXICITY AND CAUSE ENERGY DEPLETION IN NEURONS.
- Author
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Loske, C., Dringen, R., Schinzel, P., Riederer, P., and Münch, G.
- Subjects
NEURONS ,NERVOUS system ,ALZHEIMER'S disease ,AMYLOID ,NEUROSCIENCES - Abstract
The article presents an abstract of the study "Advanced Glycation Endproducts Increase βAmyloid Toxicity and Cause Energy Depletion in Neurons." It will be presented at a joint meeting of the International Society for Neurochemistry and the European Society for Neurochemistry which will be organized in Berlin, Germany, from August 8-14, 1999. The result suggests that interference with AGE-related toxicity are promising targets for a neuroprotective treatment of Alzheimer's disease.
- Published
- 1999
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