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Periventricular leukomalacia has its peak incidence at 23 to 32 weeks postconceptional age characterized by extensive oligodendrocyte migration and maturation. Oxygen toxicity has been identified as a possible contributing factor to the pathogenesis of cerebral palsy in survivors of preterm birth. 17\u03b2\u2010estradiol (E2) is important for the development and function of the central nervous system. Furthermore, neuroprotective properties have been attributed to estrogens. We examined the effect of E2 on hyperoxia\u2010induced cell death in the developing white matter in the rat brain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Six\u2010day\u2010old (P6) rat pups, the immature oligodendroglial cell line (OLN\u201093), and primary oligodendrocyte cultures were subjected to 80% O<jats:sub>2<\/jats:sub> in the presence or absence of E2 (600\u03bcg\/kg intraperitoneally in vivo, 10<jats:sup>\u22126<\/jats:sup>\u201310<jats:sup>\u221210<\/jats:sup>M in vitro). Cell counts and lactate dehydrogenase assay were used to assess cell survival. Immunoblot analysis was used for detection of estrogen receptor expression and investigation of apoptotic signaling pathways. White matter injury was assessed by myelin basic protein immunocytochemistry at P11.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>E2 produced significant dose\u2010dependent protection against oxygen\u2010induced apoptotic cell death in primary oligodendrocytes. Treatment with E2 prevented hyperoxia\u2010induced proapoptotic Fas\u2010upregulation and caspase\u20103 activation. Finally, E2 antagonized hyperoxia\u2010induced inactivation of extracellular signal\u2010regulated kinase 1 and 2 and Akt, key kinases of the mitogen\u2010activated protein kinase and phosphatidylinositol 3\u2010kinase cell survival promoting pathways, respectively. Loss of myelin basic protein labeling was seen in P11 pups after oxygen exposure, and E2 attenuated this injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These results suggest a possible role for estrogens in the prevention of neonatal oxygen\u2010induced white matter injury. Ann Neurol 2007<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.21118","type":"journal-article","created":{"date-parts":[[2007,4,11]],"date-time":"2007-04-11T18:18:25Z","timestamp":1176315505000},"page":"562-573","source":"Crossref","is-referenced-by-count":76,"title":["Estradiol attenuates hyperoxia\u2010induced cell death in the developing white 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