Suramin induces and enhances apoptosis in a model of hyperoxia-induced oligodendrocyte injury.
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 an in vitro model of hyperoxia-induced 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 microM). 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 lead 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.[1]References
- Suramin induces and enhances apoptosis in a model of hyperoxia-induced oligodendrocyte injury. Stark, S., Schuller, A., Sifringer, M., Gerstner, B., Brehmer, F., Weber, S., Altmann, R., Obladen, M., Buhrer, C., Felderhoff-Mueser, U. Neurotox. Res (2008) [Pubmed]
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