Neurotoxicity Research

, Volume 17, Issue 4, pp 317–331 | Cite as

Mechanisms Involved in the Modulation of Astroglial Resistance to Oxidative Stress Induced by Activated Microglia: Antioxidative Systems, Peroxide Elimination, Radical Generation, Lipid Peroxidation

  • Claudia Röhl
  • Elisabeth Armbrust
  • Eva Herbst
  • Anne Jess
  • Michael Gülden
  • Edmund Maser
  • Gerald Rimbach
  • Christine Bösch-Saadatmandi
Article

Abstract

Microglia and astrocytes are the cellular key players in many neurological disorders associated with oxidative stress and neuroinflammation. Previously, we have shown that microglia activated by lipopolysaccharides (LPS) induce the expression of antioxidative enzymes in astrocytes and render them more resistant to hydrogen peroxide (H2O2). In this study, we examined the mechanisms involved with respect to the cellular action of different peroxides, the ability to detoxify peroxides, and the status of further antioxidative systems. Astrocytes were treated for 3 days with medium conditioned by purified quiescent (microglia-conditioned medium, MCM[−]) or LPS-activated (MCM[+]) microglia. MCM[+] reduced the cytotoxicity of the organic cumene hydroperoxide in addition to that of H2O2. Increased peroxide resistance was not accompanied by an improved ability of astrocytes to remove H2O2 or an increased expression/activity of peroxide eliminating antioxidative enzymes. Neither peroxide-induced radical generation nor lipid peroxidation were selectively affected in MCM[+] treated astrocytes. The glutathione content of peroxide resistant astrocytes, however, was increased and superoxide dismutase and heme oxygenase were found to be upregulated. These changes are likely to contribute to the higher peroxide resistance of MCM[+] treated astrocytes by improving their ability to detoxify reactive oxygen radicals and oxidation products. For C6 astroglioma cells a protective effect of microglia-derived factors could not be observed, underlining the difference of primary cells and cell lines concerning their mechanisms of oxidative stress resistance. Our results indicate the importance of microglial–astroglial cell interactions during neuroinflammatory processes.

Keywords

Glial cell interactions Inflammation Gliosis Antioxidative enzymes Glutathione 

Notes

Acknowledgements

The authors thank Monika Grell and Rosemarie Sprang for their excellent technical assistance during these studies, and Jobst Sievers and Ralph Lucius for providing laboratory facilities.

References

  1. Armbrust E, Röhl C (2008) Time- and activation-dependency of the protective effect of microglia on astrocytes exposed to peroxide-induced oxidative stress. Toxicol In Vitro 22(5):1399–1404CrossRefPubMedGoogle Scholar
  2. Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM (1992) Ferritin: a cytoprotective antioxidant strategem of endothelium. J Biol Chem 267(25):18148–18153PubMedGoogle Scholar
  3. Benarroch EE (2005) Neuron–astrocyte interactions: partnership for normal function and disease in the central nervous system. Mayo Clin Proc 80(10):1326–1338CrossRefPubMedGoogle Scholar
  4. Benvenisti-Zarom L, Regan RF (2007) Astrocyte-specific heme oxygenase-1 hyperexpression attenuates heme-mediated oxidative injury. Neurobiol Dis 26(3):688–695CrossRefPubMedGoogle Scholar
  5. Bishop A, Marquis JC, Cashman NR, Demple B (1999) Adaptive resistance to nitric oxide in motor neurons. Free Radic Biol Med 26(7–8):978–986CrossRefPubMedGoogle Scholar
  6. Block ML, Hong J (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76(2):77–98CrossRefPubMedGoogle Scholar
  7. Bordet R, Deplanque D, Maboudou P, Puisieux F, Pu Q, Robin E, Martin A, Bastide M, Leys D, Lhermitte M, Dupuis B (2000) Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J Cereb Blood Flow Metab 20(8):1190–1196CrossRefPubMedGoogle Scholar
  8. Bruce-Keller AJ, Geddes JW, Knapp PE, McFall RW, Keller JN, Holtsberg FW, Parthasarathy S, Steiner SM, Mattson MP (1999) Anti-death properties of TNF against metabolic poisoning: mitochondrial stabilization by MnSOD. J Neuroimmunol 93(1–2):53–71CrossRefPubMedGoogle Scholar
  9. Cabell L, Ferguson C, Luginbill D, Kern M, Weingart A, Audesirk G (2004) Differential induction of heme oxygenase and other stress proteins in cultured hippocampal astrocytes and neurons by inorganic lead. Toxicol Appl Pharmacol 198(1):49–60CrossRefPubMedGoogle Scholar
  10. Chen J, Regan RF (2005) Increasing expression of heme oxygenase-1 by proteasome inhibition protects astrocytes from heme-mediated oxidative injury. Curr Neurovasc Res 2(3):189–196CrossRefPubMedGoogle Scholar
  11. Chen-Roetling J, Benvenisti-Zarom L, Regan RF (2005) Cultured astrocytes from heme oxygenase-1 knockout mice are more vulnerable to heme-mediated oxidative injury. J Neurosci Res 82(6):802–810CrossRefPubMedGoogle Scholar
  12. Chung RS, Penkowa M, Dittmann J, King CE, Bartlett C, Asmussen JW, Hidalgo J, Carrasco J, Leung YKJ, Walker AK, Fung SJ, Dunlop SA, Fitzgerald M, Beazley LD, Chuah MI, Vickers JC, West AK (2008) Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury. J Biol Chem 283(22):15349–15358CrossRefPubMedGoogle Scholar
  13. Cohen G (1985) The Fenton reaction. In: Greenwald RA (ed) CRC Handbook of methods for oxygen radical research, CRC Press, Inc., Boca Raton, FL, pp. 55–64Google Scholar
  14. Datta PK, Lianos EA (1999) Nitric oxide induces heme oxygenase-1 gene expression in mesangial cells. Kidney Int 55(5):1734–1739CrossRefPubMedGoogle Scholar
  15. Deplanque D, Patrice M, Puisieux F, Pu Q, Robin E, Martin A, Bastide M, Leys D, Lhermitte M, Dupuis B (2000) Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J Cereb Blood Flow Metab 20(8):1190–1196PubMedGoogle Scholar
  16. Desagher S, Glowinski J, Premont J (1996) Astrocytes protect neurons from hydrogen peroxide toxicity. J Neurosci 16:2553–2562PubMedGoogle Scholar
  17. Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421–431CrossRefPubMedGoogle Scholar
  18. Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62(6):649–671CrossRefPubMedGoogle Scholar
  19. Dringen R, Hamprecht B (1996) Glutathione content as an indicator for the presence of metabolic pathways of amino acids in astroglial cultures. J Neurochem 67(4):1375–1382PubMedGoogle Scholar
  20. Dringen R, Kussmaul L, Hamprecht B (1998) Detoxification of exogenous hydrogen peroxide and organic hydroperoxides by cultured astroglial cells assessed by microtiter plate assay. Brain Res Protocol 2(3):223–228CrossRefGoogle Scholar
  21. Drukarch B, Schepens E, Stoof JC, Langeveld CH, Van Muiswinkel FL (1998) Astrocyte-enhanced neuronal survival is mediated by scavenging of extracellular reactive oxygen species. Free Radic Biol Med 25(2):217–220CrossRefPubMedGoogle Scholar
  22. Duncan AJ, Heales SJR (2005) Nitric oxide and neurological disorders. Mol Aspects Med 26(1-2):67-96CrossRefPubMedGoogle Scholar
  23. Falletti O, Cadet J, Favier A, Douki T (2007) Trapping of 4-hydroxynonenal by glutathione efficiently prevents formation of DNA adducts in human cells. Free Radic Biol Med 42(8):1258–1269CrossRefPubMedGoogle Scholar
  24. Ferret P, Soum E, Negre O, Fradelizi D (2002) Auto-protective redox buffering systems in stimulated macrophages. BMC Immunol 3:3CrossRefPubMedGoogle Scholar
  25. Floden AM, Combs CK (2007) Microglia repetitively isolated from in vitro mixed glial cultures retain their initial phenotype. J Neurosci Methods 164(2):218–224CrossRefPubMedGoogle Scholar
  26. Frankel D, Mehindate K, Schipper HM (2000) Role of heme oxygenase-1 in the regulation of manganese superoxide dismutase gene expression in oxidatively-challenged astroglia. J Cell Physiol 185(1):80–86CrossRefPubMedGoogle Scholar
  27. Gallagher BM, Phelan SA (2007) Investigating transcriptional regulation of Prdx6 in mouse liver cells. Free Radic Biol Med 42(8):1270–1277CrossRefPubMedGoogle Scholar
  28. Habig WH, Jakoby WB (1981) Assays for differentiation of glutathione S-transferases. Methods Enzymol 77:398–405CrossRefPubMedGoogle Scholar
  29. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97(6):1634–1658CrossRefPubMedGoogle Scholar
  30. Hanisch U (2002) Microglia as a source and target of cytokines. Glia 40(2):140–155CrossRefPubMedGoogle Scholar
  31. Hara E, Takahashi K, Takeda K, Nakayama M, Yoshizawa M, Fujita H, Shirato K, Shibahara S (1999) Induction of heme oxygenase-1 as a response in sensing the signals evoked by distinct nitric oxide donors. Biochem Pharmacol 58(2):227–236CrossRefPubMedGoogle Scholar
  32. Hinerfeld D, Traini MD, Weinberger RP, Cochran B, Doctrow SR, Harry J, Melov S (2004) Endogenous mitochondrial oxidative stress: neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice. J Neurochem 88(3):657–667CrossRefPubMedGoogle Scholar
  33. Jiang Z, Woollard ACS, Wolff SP (1990) Hydrogen peroxide production during experimental protein glycation. FEBS Lett 268(1):69–71CrossRefPubMedGoogle Scholar
  34. Jin M, Lee Y, Kim J, Sun H, Moon E, Shong MH, Kim S, Lee SH, Lee T, Yu D, Lee D (2005) Characterization of neural cell types expressing peroxiredoxins in mouse brain. Neurosci Lett 381(3):252–257CrossRefPubMedGoogle Scholar
  35. Keller JN, Kindy MS, Holtsberg FW, St. Clair DK, Yen H, Germeyer A, Steiner SM, Bruce-Keller AJ, Hutchins JB, Mattson MP (1998) Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci 18(2):687–697PubMedGoogle Scholar
  36. Keyse SM, Tyrrell RM (1989) Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci USA 86(1):99–103CrossRefPubMedGoogle Scholar
  37. Kifle Y, Monnier J, Chesrown SE, Raizada MK, Nick HS (1996) Regulation of the manganese superoxide dismutase and inducible nitric oxide synthase gene in rat neuronal and glial cells. J Neurochem 66(5):2128–2135PubMedCrossRefGoogle Scholar
  38. Kuhlmann A, Röhl C (2006) Phenolic antioxidant compounds produced by in vitro cultures of rosemary (Rosmarinus officinalis L.) with different differentiation degrees and their anti-inflammatory effect on lipopolysaccharide-activated microglia. Pharmaceut Biol 44(6):401–410CrossRefGoogle Scholar
  39. Laird MD, Vender JR, Dhandapani KM (2008) Opposing roles for reactive astrocytes following traumatic brain injury. Neurosignals 16(2–3):154–164CrossRefPubMedGoogle Scholar
  40. Lawrence RA, Burk RF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 71(4):952–958CrossRefPubMedGoogle Scholar
  41. Linden A, Gülden M, Martin H, Maser E, Seibert H (2008) Peroxide-induced cell death and lipid peroxidation in C6 glioma cells. Toxicol In Vitro 22(5):1371–1376CrossRefPubMedGoogle Scholar
  42. Liu B, Hong J (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304(1):1–7CrossRefPubMedGoogle Scholar
  43. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT Method. Methods 25(4):402–408CrossRefPubMedGoogle Scholar
  44. Lowry OH, Rosebrough NJ, Farr JA, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275PubMedGoogle Scholar
  45. Maines MD (1997) The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 37:517–554CrossRefPubMedGoogle Scholar
  46. Makino N, Mise T, Sagara J (2008) Kinetics of hydrogen peroxide elimination by astrocytes and C6 glioma cells analysis based on a mathematical model. Biochim Biophys Acta 1780(6):927–936PubMedGoogle Scholar
  47. Manganaro F, Chopra VS, Mydlarski MB, Bernatchez G, Schipper HM (1995) Redox perturbations in cysteamine-stressed astroglia: Implications for inclusion formation and gliosis in the aging brain. Free Radic Biol Med 19(6):823–835CrossRefPubMedGoogle Scholar
  48. Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47(3):469–474CrossRefPubMedGoogle Scholar
  49. Masaki N, Kyle ME, Farber JL (1989) Tert-butyl hydroperoxide kills cultured hepatocytes by peroxidizing membrane lipids. Arch Biochem Biophys 269(2):390–399CrossRefPubMedGoogle Scholar
  50. McCarthy K, De Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85(3):890–902CrossRefPubMedGoogle Scholar
  51. Mehindate K, Sahlas DJ, Frankel D, Mawal Y, Liberman A, Corcos J, Dion S, Schipper HM (2001) Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis. J Neurochem 77(5):1386–1395CrossRefPubMedGoogle Scholar
  52. Min K, Yang M, Kim S, Jou I, Joe E (2006) Astrocytes induce hemeoxygenase-1 expression in microglia: a feasible mechanism for preventing excessive brain inflammation. J Neurosci 26(6):1880–1887CrossRefPubMedGoogle Scholar
  53. Mokuno K, Ohtani K, Suzumura A, Kiyosawa K, Hirose Y, Kawai K, Kato K (1994) Induction of manganese superoxide dismutase by cytokines and lipopolysaccharide in cultured mouse astrocytes. J Neurochem 63(2):612–616PubMedGoogle Scholar
  54. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63CrossRefPubMedGoogle Scholar
  55. Motterlini R, Green CJ, Foresti R (2002) Regulation of heme oxygenase-1 by redox signals involving nitric oxide. Antioxid Redox Signal 4(4):615–624CrossRefPubMedGoogle Scholar
  56. Mydlarski MB, Liang JJ, Schipper HM (1993) Role of the cellular stress response in the biogenesis of cysteamine-induced astrocytic inclusions in primary culture. J Neurochem 61(5):1755–1765CrossRefPubMedGoogle Scholar
  57. Nakajima K, Kohsaka S (2004) Microglia: neuroprotective and neurotrophic cells in the central nervous system. Curr Drug Targets Cardiovasc Haematol Disord 4(1):65–84CrossRefPubMedGoogle Scholar
  58. Nakaso K, Kitayama M, Mizuta E, Fukuda H, Ishii T, Nakashima K, Yamada K (2000) Co-induction of heme oxygenase-1 and peroxiredoxin I in astrocytes and microglia around hemorrhagic region in the rat brain. Neurosci Lett 293(1):49–52CrossRefPubMedGoogle Scholar
  59. Nath KA, Balla G, Vercellotti GM, Balla J, Jacob HS, Levitt MD, Rosenberg ME (1992) Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J Clin Invest 90(1):267–270CrossRefPubMedGoogle Scholar
  60. Otterbein LE, Choi AMK (2000) Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol 279(6):L1029–L1037PubMedGoogle Scholar
  61. Polte T, Abate A, Dennery PA, Schröder H (2000) Heme oxygenase-1 is a cGMP-inducible endothelial protein and mediates the cytoprotective action of nitric oxide. Arterioscler Thromb Vasc Biol 20(5):1209–1215PubMedGoogle Scholar
  62. Power JHT, Asad S, Chataway TK, Chegini F, Manavis J, Temlett JA, Jensen PH, Blumbergs PC, Gai W (2008) Peroxiredoxin 6 in human brain: molecular forms, cellular distribution and association with Alzheimer’s disease pathology. Acta Neuropathol 115(6):611–622CrossRefPubMedGoogle Scholar
  63. Röhl C, Sievers J (2005) Microglia is activated by astrocytes in trimethyltin intoxication. Toxicol Appl Pharmacol 204(1):36–45CrossRefPubMedGoogle Scholar
  64. Röhl C, Held-Feindt J, Sievers J (2003) Developmental changes of parameters for astrogliosis during cultivation of purified cerebral astrocytes from newborn rats. Develop Brain Res 144(2):191–199CrossRefGoogle Scholar
  65. Röhl C, Lucius R, Sievers J (2007) The effect of activated microglia on astrogliosis parameters in astrocyte cultures. Brain Res 1129:43–52CrossRefPubMedGoogle Scholar
  66. Röhl C, Armbrust E, Kolbe K, Lucius R, Maser E, Venz S, Gülden M (2008) Activated microglia modulate astroglial enzymes involved in oxidative and inflammatory stress and increase the resistance of astrocytes to oxidative stress in vitro. Glia 56(10):1114–1126CrossRefPubMedGoogle Scholar
  67. Rojo LE, Fernández JA, Maccioni AA, Jimenez JM, Maccioni RB (2008) Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 39(1):1–16CrossRefPubMedGoogle Scholar
  68. Srisook K, Cha Y (2004) Biphasic induction of heme oxygenase-1 expression in macrophages stimulated with lipopolysaccharide. Biochem Pharmacol 68(9):1709–1720CrossRefPubMedGoogle Scholar
  69. Srisook K, Jung N, Kim B, Cha S, Kim H, Cha Y (2005) Heme oxygenase-1-mediated partial cytoprotective effect by NO on cadmium-induced cytotoxicity in C6 rat glioma cells. Toxicol In Vitro 19(1):31–39CrossRefPubMedGoogle Scholar
  70. Streit WJ (2005) Microglia and neuroprotection: implications for Alzheimer’s disease. Brain Res Brain Res Rev 48(2):234–239CrossRefPubMedGoogle Scholar
  71. Tenhunen R, Marver HS, Schmid R (1969) Microsomal heme oxygenase. Characterization of the enzyme. J Biol Chem 244(23):6388–6394PubMedGoogle Scholar
  72. Terry CM, Clikeman JA, Hoidal JR, Callahan KS (1998) Effect of tumor necrosis factor-alpha and interleukin-1 alpha on heme oxygenase-1 expression in human endothelial cells. Am J Physiol 274(3 Pt 2):H883–H891PubMedGoogle Scholar
  73. Tietze F (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 27(3):502–522CrossRefPubMedGoogle Scholar
  74. Traystman RJ, Kirsch JR, Koehler RC (1991) Oxygen radical mechanisms of brain injury following ischemia and reperfusion. J Appl Physiol 71(4):1185–1195PubMedGoogle Scholar
  75. Trendelenburg G, Dirnagl U (2005) Neuroprotective role of astrocytes in cerebral ischemia: Focus on ischemic preconditioning. Glia 50(4):307–320CrossRefPubMedGoogle Scholar
  76. Tsukiji T, Takahashi T, Mizobuchi S, Suzuki T, Hirakawa M, Watanabe S, Akagi R (2000) Gene expression of heme oxygenase-1 during glial activation by lipopolysaccharide. Res Commun Mol Pathol Pharmacol 107(3–4):187–196PubMedGoogle Scholar
  77. Visner GA, Dougall WC, Wilson JM, Burr IA, Nick HS (1990) Regulation of manganese superoxide dismutase by lipopolysaccharide, interleukin-1, and tumor necrosis factor. Role in the acute inflammatory response. J Biol Chem 265(5):2856–2864PubMedGoogle Scholar
  78. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S (1999) Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 103(1):129–135CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Claudia Röhl
    • 1
    • 2
  • Elisabeth Armbrust
    • 1
    • 2
  • Eva Herbst
    • 2
  • Anne Jess
    • 1
  • Michael Gülden
    • 1
  • Edmund Maser
    • 1
  • Gerald Rimbach
    • 3
  • Christine Bösch-Saadatmandi
    • 3
  1. 1.Institute of Toxicology and Pharmacology for Natural ScientistsChristian-Albrechts-UniversityKielGermany
  2. 2.Department of AnatomyChristian-Albrechts-UniversityKielGermany
  3. 3.Institute of Human Nutrition and Food ScienceChristian-Albrechts-UniversityKielGermany

Personalised recommendations