GPR30 activation is neither necessary nor sufficient for acute neuroprotection by 17β-estradiol after an ischemic injury in organotypic hippocampal slice cultures

• 17β-estradiol was most significantly neuroprotective at the physiological dose of 100 pM.
• Inhibition of GPR30 did not significantly decrease neuroprotection.
• Direct GPR30 activation provided no neuroprotection.
• The physiological concentration of 100 pM E2 did not activate GPR30 receptors.
• GPR30 activation is neither necessary nor sufficient for E2-mediated neuroprotection.

In this study, we investigated the role of GPR30 in 17β-estradiol- (E2) mediated neuroprotection after an ischemic injury in an organotypic hippocampal slice culture (OHSC) model. We report that after oxygen–glucose deprivation (OGD), a physiological concentration of 100 pM E2 provided the greatest significant reduction in cell death while supra-physiological levels were less effective. The canonical estrogen receptor (ER) inhibitor ICI 182,780 completely abrogated the therapeutic effect of E2 while the GPR30 antagonist G−15 effected a slight but not significant reduction in neuroprotection. Only supra-physiological levels of E2 led to significantly increased phosphorylation of Akt and Erk which are well known downstream effects of GPR30 activation. We conclude that GPR30 activation may facilitate acute E2 mediated neuroprotection after OGD, but is neither necessary nor sufficient.