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Suramin induces and enhances apoptosis in a model of hyperoxia-induced oligodendrocyte injury

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Abstract

Recent evidence suggests oxygen as a powerful trigger for cell death in the immature white matter, leading to periventricular leukomalacia (PVL) as a cause of adverse neurological outcome in survivors of preterm birth. This oligodendrocyte (OL) death is associated with oxidative stress, upregulation of apoptotic signaling factors (i.e., Fas, caspase-3) and decreased amounts of neurotrophins. In search of neuroprotective strategies we investigated whether the polysulfonated urea derivative suramin, recently identified as a potent inhibitor of Fas signaling, affords neuroprotection in anin vitro model of hyperoxiainduced injury to immature oligodendrocytes.

Immature OLs (OLN-93) were subjected to 80% hyperoxia (48 h) in the presence or absence of suramin (0, 30, 60, 120 μM). Cell death was assessed by flow cytometry (Annexin V, caspase-3 activity assay) and immunohistochemistry for activated caspase-3. Immunoblotting for the death receptor Fas, cleaved caspase-8 and the phosphorylated isoform of the serine-threonin kinase Akt (pAkt) was performed.

Suramin led to OL apoptosis and potentiated hyperoxia-induced injury in a dose-dependent manner. Immunoblotting revealed increased Fas and caspase-8 expression by suramin treatment. This effect was significantly enhanced when suramin was combined with hyperoxia. Furthermore, pAkt levels decreased following suramin exposure, indicating interference with neurotrophin-dependent growth factor signaling.

These data indicate that suramin causes apoptotic cell death and aggravates hyperoxia-induced cell death in immature OLs. Its mechanism of action includes an increase of previously described hyperoxia-induced expression of pro-apoptotic factors and deprivation of growth factor dependent signaling components.

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References

  • Bezvenyuk Z, T Suuronen, A Salminen and V Solovyan (2000) Protective effect of suramin against cell death in rat cerebellar granular neurons and mouse neuroblastoma cells.Neurosci. Lett. 292, 111–114.

    Article  PubMed  CAS  Google Scholar 

  • Chan CF and SY Lin-Shiau (2000) Site of action of suramin and reactive blue 2 in preventing neuronal death induced by dequalinium.J. Neurosci. Res. 62, 692–699.

    Article  PubMed  CAS  Google Scholar 

  • Collins MP, JM Lorenz, JR Jetton and N Paneth (2001) Hypocapnia and other ventilation-related risk factors for cerebral palsy in low birth weight infants.Pediatr. Res. 50, 712–719.

    Article  PubMed  CAS  Google Scholar 

  • Curtin JF and TG Cotter (2003) Live and let die: regulatory mechanisms in Fas-mediated apoptosis.Cell Signal 15, 983–992.

    Article  PubMed  CAS  Google Scholar 

  • Eichhorst ST, S Muerkoster, MA Weigand and PH Krammer (2001) The chemotherapeutic drug 5-fluouracil induces apoptosis in mouse thymocytesin vivo via activation of the CD95(Apo-1/Fas) system.Cancer Res. 61, 243–248.

    PubMed  CAS  Google Scholar 

  • Eichhorst ST, A Krueger, S Muerkoster, SC Fas, A Golks, U Gruetzner, L Schubert, C Opelz, M Bilzer, AL Gerbes and PH Krammer (2004) Suramin inhibits death receptorinduced apoptosisin vitro and fulminant apoptotic liver damage in mice.Nat. Med. 10, 602–609.

    Article  PubMed  CAS  Google Scholar 

  • Felderhoff-Mueser U, DL Taylor, K Greenwood, M Kozma, D Stibenz, UC Joashi, AD Edwards and H Mehmet (2000) Fas/ CD95/APO-1 can function as a death receptor for neuronal cellsin vitro andin vivo and is upregulated following cerebral hypoxic-ischemic injury to the developing rat brain.Brain Pathol. 10, 17–29.

    Article  PubMed  CAS  Google Scholar 

  • Felderhoff-Mueser U, P Bittigau, M Sifringer, B Jarosz, E Korobowicz, L Mahler, T Piening, A Moysich, T Grune, F Thor, R Heumann, C Buhrer and C Ikonomidou (2004) Oxygen causes cell death in the developing brain.Neurobiol. Dis. 17, 273–282.

    Article  PubMed  CAS  Google Scholar 

  • Felderhoff-Mueser U, M Sifringer, O Polley, M Dzietko, B Leineweber, L Mahler, M Baier, P Bittigau, M Obladen, C Ikonomidou and C Buhrer (2005) Caspase-1-processed interleukins in hyperoxia-induced cell death in the developing brain.Ann. Neurol. 57, 50–59.

    Article  PubMed  CAS  Google Scholar 

  • Fischer U, RU Janicke and K Schulze-Osthoff (2003) Many cuts to ruin: a comprehensive update of caspase substrates.Cell Death Differ. 10, 76–100.

    Article  PubMed  CAS  Google Scholar 

  • Gerstner B, A Gratopp, M Marcinkowski, M Sifringer, M Obladen and C Buhrer (2005) Glutaric acid and its metabolites cause apoptosis in immature oligodendrocytes: a novel mechanism of white matter degeneration in glutaryl-CoA dehydrogenase deficiency.Pediatr. Res. 57, 771–776.

    Article  PubMed  CAS  Google Scholar 

  • Gerstner B, C Buhrer, C Rheinlander, O Polley, A Schuller, M Berns, M Obladen and U Felderhoff-Mueser (2006) Maturation-dependent oligodendrocyte apoptosis caused by hyperoxia.J. Neurosci. Res. 84, 306–315.

    Article  PubMed  CAS  Google Scholar 

  • Gerstner B, M Sifringer, M Dzietko, A Schuller, J Lee, S Simons, M Obladen, JJ Volpe, PA Rosenberg and U Felderhoff-Mueser (2007) Estradiol attenuates hyperoxiainduced cell death in the developing white matter.Ann. Neurol. 61, 562–573.

    Article  PubMed  CAS  Google Scholar 

  • Gill JS and AJ Windebank (1998) Suramin induced ceramide accumulation leads to apoptotic cell death in dorsal root ganglion neurons.Cell Death Differ. 5, 876–883.

    Article  PubMed  CAS  Google Scholar 

  • Gill JS and AJ Windebank (2000) Ceramide initiates NFκBmediated caspase activation in neuronal apoptosis.Neurobiol. Dis. 7, 448–461.

    Article  PubMed  CAS  Google Scholar 

  • Gorospe M, X Wang, KZ Guyton and NJ Holbrook (1996) Protective role of p21(Waf1/Cip1) against prostaglandin A2-mediated apoptosis of human colorectal carcinoma cells.Mol. Cell. Biol. 16, 6654–6660.

    PubMed  CAS  Google Scholar 

  • Goto T, S Takeuchi, K Miura, S Ohshima, K Mikami, K Yoneyama, M Sato, T Shibuya, D Watanabe, E Kataoka, D Segawa, A Endo, W Sato, R Yoshino and S Watanabe (2006) Suramin prevents fulminant hepatic failure resulting in reduction of lethality through the suppression of NF-κB activity.Cytokine 33, 28–35.

    Article  PubMed  CAS  Google Scholar 

  • Gritli-Linde A, JV Ruch, MP Mark, S Lecolle and M Goldberg (1994) Effects of suramin, a polyanionic drug inducing lysosomal storage disorders on tooth germsin vitro. Biol. Cell 81, 143–152.

    CAS  Google Scholar 

  • Hintz SR, DE Kendrick, BR Vohr, WK Poole and RD Higgins (2005) Changes in neurodevelopmental outcomes at 18 to 22 months’ corrected age among infants of less than 25 weeks’ gestational age born in 1993-1999.Pediatrics 115, 1645–1651.

    Article  PubMed  Google Scholar 

  • Kaplan DR and FD Miller (2000) Neurotrophin signal transduction in the nervous system.Curr. Opin. Neurobiol. 10, 381–391.

    Article  PubMed  CAS  Google Scholar 

  • Kathir KM, TK Kumar and C Yu (2006) Understanding the mechanism of the antimitogenic activity of suramin.Biochemistry 45, 899–906.

    Article  PubMed  CAS  Google Scholar 

  • Kaur C, V Sivakumar, LS Ang and A Sundaresan (2006) Hypoxic damage to the periventricular white matter in neonatal brain: role of vascular endothelial growth factor, nitric oxide and excitotoxicity.J. Neurochem. 98, 1200–1216.

    Article  PubMed  CAS  Google Scholar 

  • Kharlamov A, SC Jones and DK Kim (2002) Suramin reduces infarct volume in a model of focal brain ischemia in rats.Exp. Brain Res. 147, 353–359.

    Article  PubMed  CAS  Google Scholar 

  • Kruidering M and GI Evan (2000) Caspase-8 in apoptosis: the beginning of “the end”?IUBMB Life 50, 85–90.

    PubMed  CAS  Google Scholar 

  • La Rocca RV, CA Stein and CE Myers (1990) Suramin: prototype of a new generation of antitumor compounds.Cancer Cells 2, 106–115.

    PubMed  Google Scholar 

  • Marlow N, D Wolke, MA Bracewell and M Samara (2005) Neurologic and developmental disability at six years of age after extremely preterm birth.N. Engl. J. Med. 352, 9–19.

    Article  PubMed  CAS  Google Scholar 

  • Mitsuya H, M Popovic, R Yarchoan, S Matsushita, RC Gallo and S Broder (1984) Suramin protection of T cellsin vitro against infectivity and cytopathic effect of HTLV-III.Science 226, 172–174.

    Article  PubMed  CAS  Google Scholar 

  • Richter-Landsberg C and M Heinrich (1996) OLN-93: a new permanent oligodendroglia cell line derived from primary rat brain glial cultures.J. Neurosci. Res. 45, 161–173.

    Article  PubMed  CAS  Google Scholar 

  • Rolland A and B Thylefors (1982) Basis for treatment and prevention of ocular onchocerciasis.Rev. Int. Trach. Pathol. Ocul. Trop. Subtrop. Sante Publique 1–156.

  • Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways.EMBO J. 17, 1675–1687.

    Article  PubMed  CAS  Google Scholar 

  • Sirinyan M, F Sennlaub, A Dorfman, P Sapieha, F Gobeil Jr, P Hardy, P Lachapelle and S Chemtob (2006) Hyperoxic exposure leads to nitrative stress and ensuing microvascular degeneration and diminished brain mass and function in the immature subject.Stroke 37, 2807–2815.

    Article  PubMed  CAS  Google Scholar 

  • Suda T and S Nagata (1994) Purification and characterization of the Fas-ligand that induces apoptosis.J. Exp. Med. 179, 873–879.

    Article  PubMed  CAS  Google Scholar 

  • Sullivan KA, B Kim, M Buzdon and EL Feldman (1997) Suramin disrupts insulin-like growth factor-II (IGF-II) mediated autocrine growth in human SH-SY5Y neuroblastoma cells.Brain Res. 744, 199–206.

    Article  PubMed  CAS  Google Scholar 

  • Taha TA, TD Mullen and LM Obeid (2006) A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death.Biochim. Biophys. Acta 1758, 2027–2036.

    Article  PubMed  CAS  Google Scholar 

  • Voogd TE, EL Vansterkenburg, J Wilting and LH Janssen (1993) Recent research on the biological activity of suramin.Pharmacol. Rev. 45, 177–203.

    PubMed  CAS  Google Scholar 

  • Wang X, CI Rousset, H Hagberg and C Mallard (2006) Lipopolysaccharide-induced inflammation and perinatal brain injury.Semin. Fetal Neonatal Med. 11, 343–353.

    Article  PubMed  Google Scholar 

  • Zhuang S and RG Schnellmann (2005) Suramin promotes proliferation and scattering of renal epithelial cells.J. Pharmacol. Exp. Ther. 314, 383–390.

    Article  PubMed  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Neonatology, Campus Virchow-Klinikum, Charité, Universitätsmedizin Berlin, D-13353, Berlin, Germany

    Simone Stark, Alexandra SchÜller, Marco Sifringer, Bettina Erstner, Felix Brehmer, Sven Weber, Rodica Altmann, Michael Obladen & Ursula Felderhoff-Mueser

  2. Department of Pediatrics, Catholic Children’s Hospital Wilhelmstift, D-22149, Hamburg, Germany

    Simone Stark

  3. Department of Neonatology, Basel University Children’s Hospital, Basel, Switzerland

    Christoph BÜhrer

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  1. Simone Stark
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  2. Alexandra SchÜller
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  3. Marco Sifringer
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  4. Bettina Erstner
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  5. Felix Brehmer
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  6. Sven Weber
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  7. Rodica Altmann
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  8. Michael Obladen
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  9. Christoph BÜhrer
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  10. Ursula Felderhoff-Mueser
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Correspondence to Ursula Felderhoff-Mueser.

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Stark, S., SchÜller, A., Sifringer, M. et al. Suramin induces and enhances apoptosis in a model of hyperoxia-induced oligodendrocyte injury. neurotox res 13, 197–207 (2008). https://doi.org/10.1007/BF03033503

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  • DOI: https://doi.org/10.1007/BF03033503

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