Hypoxia-induced apoptotic cell death is prevented by oestradiol via oestrogen receptors in the developing central nervous system

POZO DEVOTO, V M; GIUSTI, SEBASTIAN; CHAVEZ, J C; FISZER DE PLAZAS, S

JOURNAL OF NEUROENDOCRINOLOGY.

Año: 2008 vol. 20 p. 375 - 380

0953-8194

The neuroprotective effects of oestrogens have been demonstrated against a variety of insults,including excitotoxicity, oxidative stress and cerebral ischemia under certain conditions. However,the molecular mechanisms underlying oestrogen neuroprotection are still unclear. We aimed todetermine whether 17b-oestradiol (E2) administration post-hypoxia (p-hx) was neuroprotectiveand whether these actions were mediated through oestrogen receptors (ER). For this purpose,12-embyonic day-old chickens were subjected to acute hypoxia [8% (O2), 60 min], followed bydifferent reoxygenation periods. To test the neuroprotective effect of E2 and its mechanism,embryos were injected 30 min after the end of hypoxia with E2 alone or with ICI 182 780, acompetitive antagonist of ER. Cytochrome c (cyt c) release, an indicator of mitochondrial apoptoticpathway, was measured by western blot in optic lobe cytosolic extracts. DNA fragmentationby TUNEL fluorescence and caspase-3 fragmentation by immunofluorescence were detected onoptic lobe sections. Acute hypoxia produces a significant increase in cyt c release from mitochondriaat 4 h p-hx, followed by an increase in TUNEL positive cells 2 h later (6 h p-hx).Administration of E2 (0.5 mg⁄ egg) produced a significant decrease in cytosolic cyt c levels at4 h p-hx, in casapse-3 activation and in TUNEL positive cells at 6 h p-hx compared to vehicletreated embryos. In the E2-ICI 182 780 treated embryos, cyt c release, caspase-3 fragmentationand TUNEL positive cells were similar to the hypoxic embryos, thus suggesting the requirementof an E2–ER interaction for E2 mediated neuroprotective effects. In conclusion, E2 preventshypoxia-induced cyt c release and posterior cell death and these effects are mediated byoestrogen receptors.