Estradiol attenuates hyperoxia-induced cell death in the developing white matter

• Published in: Annals of neurology 2007-06, Vol.61 (6), p.562-573
• Main Authors: Gerstner, Bettina, Sifringer, Marco, Dzietko, Mark, Schüller, Alexandra, Lee, Joan, Simons, Sinno, Obladen, Michael, Volpe, Joseph J., Rosenberg, Paul A., Felderhoff-Mueser, Ursula
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Apoptosis - drug effects; Biological and medical sciences; Brain - drug effects; Brain - pathology; Brain Damage, Chronic - pathology; Brain Damage, Chronic - prevention & control; Caspase 3 - metabolism; Cell Survival - drug effects; Cells, Cultured; Corpus Callosum - drug effects; Corpus Callosum - pathology; Disease Models, Animal; Drug toxicity and drugs side effects treatment; Enzyme Activation - drug effects; Estradiol - pharmacology; Estrogen Receptor alpha - biosynthesis; Estrogen Receptor beta - biosynthesis; Hyperoxia - drug therapy; Hyperoxia - metabolism; Medical sciences; Neurology; Neuropharmacology; Neuroprotective agent; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Oligodendroglia - pathology; Oxygen - toxicity; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Rats, Wistar; Toxicity: nervous system and muscle
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21118

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. 17β‐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% O2 in the presence or absence of E2 (600μg/kg intraperitoneally in vivo, 10−6–10−10M 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. Interpretation These results suggest a possible role for estrogens in the prevention of neonatal oxygen‐induced white matter injury. Ann Neurol 2007