Coupling of GPR30 mediated neurogenesis and protection with astroglial Aromatase-STAT3 signaling in rat hippocampus after global cerebral ischemia.

Our previous study revealed that G-protein-coupled estrogen receptor-30 (GPR30) agonist G1 serves as a viable alternative neuroprotectant of 17β-estradiol (E2) to attenuate neuroinflammation and improve cognitive function after global cerebral ischemia (GCI). Aromatase, the key enzyme of E2 biosynthesis, is widely expressed in animal and human brain, and its expression and activity are mediated by selective estrogen receptor modulators. In the present study, we explored the long-term protective and reparative effects of G1 in ovariectomized rats after GCI. We used the aromatase inhibitor letrozole to elucidate whether G1 and brain-derived E2 together induce beneficial effects. Our results showed that G1 administration for 28 days a) significantly increased neurogenesis in the hippocampal sub-granular zone and CA1 regions; b) declined CA1 neuronal impairment in a long-term fashion; c) enhanced expression of synaptic proteins and cognitive function; d) and prevented reactive astrocytes loss, wherein aromatase and brain-derived estrogen levels were markedly increased. Additionally, expression and activation of transducer and activator of transcription 3 (STAT3) were increased in CA1 astrocytes of G1-treated animals. Letrozole abolished all of the observed benefits of G1. Our results suggest that GPR30 activation mediates long-term neuroprotection and neurogenesis in the hippocampus following GCI, with potential mechanism coupling with the activation of astroglial aromatase-STAT3 signaling.