New mechanism of GPR30 agonist and brain-derived estrogen synergistically reducing ischemic brain damage

Our recent studies have shown that aromatase (Aro), the key enzyme to synthetize 17β-estradiol exhibits high expression in the injured brain, and the brain-derived estradiol (BDE2) triggers innate immunity response to protect against secondary neuronal apoptosis. Translationally, an important goal would be to identify mechanisms and potential therapies that can induce BDE2 in the brain so as to provide endogenous CNS protection from secondary apoptosis that occurs in neurodegenerative disorders. In pursuance of this goal, we are going to focus on the membrane estrogen receptor GPR30 that might be an important novel regulator of BDE2 in the brain, and examine the potential synergistic action between GPR30 specific agonist G1 and BDE2 to attenuate inflammatory injury following global cerebral ischemia (GCI) in surgical menopausal rats. The aims of our study would thus test the following hypotheses: 1)G1 replacement upregulates Aro protein expression and activity in the hippocampus through a GPR30-mediated mechanism, which decreases the secondary apoptotic neuron; 2)Synergistic action between G1 and BDE2 targets GPR30 activation to attenuate astrogliosis and inflammasome formation, as well as enhance anti-inflammatory cytokines; 3)Synergism between G1 and BDE2 also promotes microglia polarization from M1 to M2 phenotype, which favors neuronal repair following GCI; and 4)The AKT/PTEN-NFkB rapid signaling pathway induced by GPR30 is an important mechanism to provide neuroprotective and repair roles for synergism between G1 and BDE2 following GCI. If successful, the proposed studies could significantly advance the field by revealing novel functions of GPR30 and BDE2 against cerebral ischemic injury, which could have important translational significance.