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Estradiol attenuates hyperoxia-induced cell death in the developing white matter
Bettina Gerstner1, Marco Sifringer, Mark Dzietko
1Department of Neonatology, Charité Campus Virchow-Klinikum, Berlin, Germany. bettina.gerstner@charite.de
Insights
17beta-estradiol (E2) protects developing white matter from oxygen-induced injury in rat models. This estrogen treatment reduced cell death and preserved myelin, suggesting a potential role in preventing cerebral palsy.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Periventricular leukomalacia is a primary brain injury in preterm infants linked to cerebral palsy.
- Oxygen toxicity is a suspected contributor to brain injury and cerebral palsy in preterm infants.
- Estrogens, including 17beta-estradiol (E2), are known to have neuroprotective effects.
Purpose of the Study:
- To investigate the effect of 17beta-estradiol (E2) on hyperoxia-induced cell death in the developing white matter of rat brains.
- To determine if E2 can prevent oxygen-induced white matter injury in a neonatal rat model.
Main Methods:
- Rat pups, oligodendrocyte cell lines, and primary cultures were exposed to 80% oxygen with or without E2.
- Cell survival was assessed using cell counts and lactate dehydrogenase assays.
- Apoptotic pathways, estrogen receptor expression, and myelin basic protein were analyzed.
Main Results:
- E2 demonstrated dose-dependent protection against oxygen-induced apoptotic cell death in oligodendrocytes.
- E2 treatment inhibited hyperoxia-induced upregulation of Fas and activation of caspase-3.
- E2 prevented the inactivation of ERK1/2 and Akt survival pathways and attenuated myelin basic protein loss.
Conclusions:
- Estrogens may play a role in preventing neonatal white matter injury caused by oxygen exposure.
- E2's neuroprotective effects involve modulating apoptotic and survival signaling pathways.
- These findings support the potential therapeutic use of estrogens in preterm infants at risk for brain injury.
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.
Interpretation:
These results suggest a possible role for estrogens in the prevention of neonatal oxygen-induced white matter injury.
