title: Estradiol attenuates hyperoxia-induced cell death in the developing white matter.
abstract: OBJECTIVE
  Periventricular leukomalacia is the predominant type of brain injury in preterm infants underlying the development of cerebral palsy. 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. 17beta-estradiol (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-induced cell death in the developing white matter in the rat brain.
  
  
  METHODS
  Six-day-old (P6) rat pups, the immature oligodendroglial cell line (OLN-93), and primary oligodendrocyte cultures were subjected to 80% O(2) in the presence or absence of E2 (600 microg/kg intraperitoneally in vivo, 10(-6)-10(-10)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.
  
  
  RESULTS
  E2 produced significant dose-dependent protection against oxygen-induced apoptotic cell death in primary oligodendrocytes. Treatment with E2 prevented hyperoxia-induced proapoptotic Fas-upregulation and caspase-3 activation. Finally, E2 antagonized hyperoxia-induced inactivation of extracellular signal-regulated kinase 1 and 2 and Akt, key kinases of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase cell survival promoting pathways, respectively. Loss of myelin basic protein labeling was seen in P11 pups after oxygen exposure, and E2 attenuated this injury.
  
  
  CONCLUSIONS
  These results suggest a possible role for estrogens in the prevention of neonatal oxygen-induced white matter injury.
authors.affiliation: Department of Neonatology, Charité Campus Virchow-Klinikum, Berlin, Germany. bettina.gerstner@charite.de
authors.forename: Bettina
authors.initials: B
authors.lastname: Gerstner
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.forename: Mark
authors.initials: M
authors.lastname: Dzietko
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schüller
authors.forename: Joan
authors.initials: J
authors.lastname: Lee
authors.forename: Sinno
authors.initials: S
authors.lastname: Simons
authors.forename: Michael
authors.initials: M
authors.lastname: Obladen
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Volpe
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rosenberg
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Mueser
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001925:Brain Damage, Chronic / Q000473:pathology / Q000517:prevention & control*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003337:Corpus Callosum / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D047629:Estrogen Receptor beta / Q000096:biosynthesis; D018496:Hyperoxia / Q000188:drug therapy* / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004958:Estradiol; D053148:Caspase 3; D010100:Oxygen