17β‐Estradiol attenuates hyperoxia‐induced apoptosis in mouse C8‐D1A cell line

Abstract

In premature infants, oxygen free radicals generated following neonatal resuscitation are associated with subsequent diseases such as retinopathy of prematurity and bronchopulmonary dysplasia. Recent studies in brain tissue samples have shown that nonphysiologic oxygen levels play a key role in induction of apoptosis in the developing brain. Estrogen is a well-established agent in neuroprotection and, therefore, is thought to be neuroprotective even in the premature brain. Astrocytes appear to have a critical role in protection and survival of neurons in the brain. As one of the glial cell types, they have a great potential for possible involvement in the mediation of estrogen neuroprotective effects. The aim of our study was to analyze whether astrocytes in cell cultures are damaged by hyperoxia and whether 17beta-estradiol (E2) can protect them against apoptosis. Additionally, we investigated the mechanism of the protection by E2, hypothesizing that it is mediated through extracellular signal-regulated kinase (ERK1/2). Cells underwent eightfold more apoptosis when cultivated in hyperoxia compared with normoxia. Addition of E2 reduced apoptosis in hyperoxia by more than 50%. Levels of ERK1/2 and phosphorylated ERK1/2 were increased after hyperoxia compared with normoxia. Preincubation with E2 prior to exposure to hyperoxia resulted in decreased levels of ERK1/2 and pERK1/2. Hyperoxia induces apoptosis in C8-D1A cells, and E2 seems to be a protecting factor for astrocytes in hyperoxia. This effect is not mediated through up-regulation of pERK1/2.

Estrogen therapy to treat retinopathy in newborn mice

“…cular diseases, such as hypertension and atherosclerosis, by dilating blood vessels and increasing blood flow (28). E 2 may increase the activity of endothelial cells, inhibit endothelial cell apoptosis, promote endothelial cell proliferation, facilitate angiogenesis and the growth of blood vessels and play an important role in retinal vascular development (29,30,33).…”

“…In a previous study, we found that ER-mediated E 2 plays an important role in normal retinal vascular development and ROP pathogenesis (35). Maternal E 2 levels during pregnancy may increase by ~100-fold (33,(35)(36)(37)(38)(39). Fetal E 2 levels increase with gestational age, with the E 2 concentration peaking between 33 and 36 weeks of pregnancy.…”

“…A number of clinical trials have evaluated E 2 replacement therapy in premature infants (29,(31)(32)(33). Extremely low birth weight neonates with an average gestational age of 26.6 weeks and a birth weight of 675 g received E 2 supplementation at an intravenous dose of 2.3 mg/kg/day.…”

“…If the intravenous infusion could not be maintained, transepidermal administration was used instead. The total duration of treatment was 6 weeks to maintain the plasma E 2 at the intrauterine level (33). The neonates were followed-up until 15 months of corrected gestational age (34).…”

“…The neonates were followed-up until 15 months of corrected gestational age (34). Following drug administration, the uterine volume, breast, weight, length and head circumference of the neonates showed a transient increase and the bone mineral deposition rate trended towards an increase (33,35). The incidence of chronic lung diseases decreased and complications of the central nervous system were reduced (33,35).…”