Suppressive effects of 17β-estradiol on tributyltin-induced neuronal injury via Akt activation and subsequent attenuation of oxidative stress

AimsNeuroactive steroids are reported to protect neurons from various harmful compounds; however, the protective mechanisms remain largely unclear. In this study, we examined the suppressive effects of 17β-estradiol (E2) on tributyltin (TBT)-induced neurotoxicity.Main methodsOrganotypic hippocampal slices were prepared from neonatal rats and then cultured. Cell death was assayed by propidium iodide uptake. Levels of reactive oxygen species (ROS) were determined by dihydroethidium staining. Protein phosphorylation was evaluated by immunoblotting.Key findingsPretreatment of the slices with E2 dose-dependently attenuated the neuronal injury induced by TBT. An estrogen receptor antagonist, ICI182,780 abrogated these neuroprotective effects. The de novo protein synthesis inhibitors actinomycin D and cycloheximide showed no effects on the neuroprotective mechanism, indicating that a nongenomic pathway acting via the estrogen receptor may be involved in the neuroprotection conferred by E2. E2 suppressed the ROS production and lipid peroxidation induced by TBT, and these effects were almost completely canceled by ICI182,780. TBT decreased Akt phosphorylation, and this reduction was suppressed by E2. An Akt inhibitor, triciribine, attenuated the decreases in both the ROS production and neuronal injury mediated by E2.SignificanceE2 enhances the phosphorylation of Akt, thereby attenuating the oxidative stress and subsequent neuronal injury induced by TBT.