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.
Stark
Simone
S
Department of Neonatology, Campus Virchow-Klinikum, Charité, Universitätsmedizin Berlin, D-13353 Berlin, Germany.
Schuller
Alexandra
A
Sifringer
Marco
M
Gerstner
Bettina
B
Brehmer
Felix
F
Weber
Sven
S
Altmann
Rodica
R
Obladen
Michael
M
Buhrer
Christoph
C
Felderhoff-Mueser
Ursula
U
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002461:Cell Line, Transformed; D003124:Colorimetry / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018496:Hyperoxia / Q000473:pathology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013498:Suramin / Q000633:toxicity*; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism
D017304:Annexin A5; D000970:Antineoplastic Agents; D019014:fas Receptor; D013498:Suramin; D053148:Caspase 3; D053181:Caspase 8