title: Rescue from Sexually Dimorphic Neuronal Cell Death by Estradiol and PI3 Kinase Activity.
abstract: Responses of primary hippocampal and cortical neurons derived from male and female rats to cellular stressors were studied. It is demonstrated that 17β-estradiol (E2), a potent neuroprotectant, protected the female neurons but had no effects on the male neurons from CoCl2- and glutamate-induced toxicity. Agonists of the estrogen receptor (ER) subtypes ERα and ERβ, DPN and PPT, respectively, had similar effects to E2. By contrast, effects of E2 were abolished by the ER antagonist ICI-182780, further corroborating the neuroprotective role of ERs. In male neurons, CoCl2 predominately activated the apoptosis-inducing factor (AIF)-dependent pathway and AIF translocation from the cytosol to the nucleus. In comparison, CoCl2 activated the caspase pathway and cytochrome c release in female neurons. The inhibitors of these pathways, namely DiQ for AIF and zVAD for caspase, specifically rescued CoCl2-induced cell death in male and female neurons, respectively. When zVAD and ICI-182780, and E2 were applied in combination, it was demonstrated E2 acted on the caspase pathway leading to female-specific neuroprotection. Furthermore, the PI3 kinase (PI3K) inhibitor blocked the rescue effects of DiQ and zVAD on the male and female neurons, respectively, suggesting that PI3K is a common upstream regulator for both pathways. The present study suggested that both sex-specific and nonspecific mechanisms played a role in neuronal responses to stressors and protective reagents.
authors.affiliation: Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. hycheng21@gmail.com.
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Shin-Hui
authors.initials: SH
authors.lastname: Hung
authors.affiliation: Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan. justinpjchu@gmail.com.|Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan. justinpjchu@gmail.com.
authors.forename: Po-Ju
authors.initials: PJ
authors.lastname: Chu
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D004958:Estradiol; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases
keywords: 17β-Estradiol; Apoptosis-inducing factor; Caspase; Estrogen receptor; Neuroprotection; Sexual dimorphism