Anti-Inflammatory Actions of G-Protein-Coupled Estrogen Receptor 1 (GPER) and Brain-Derived Estrogen Following Cerebral Ischemia in Ovariectomized Rats

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  • 作者:Jing Xu, Jing Bai, Fujia Gao, Chao Xu, Yuanyuan Huang, Danyang Li, Lu Wang, Ruimin Wang
  • 期刊:Biology-Basel
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Simple SummaryThe overall goal of this study was to examine the role of G-protein-coupled estrogen receptor 1 signaling in the regulation of the early inflammatory process following global cerebral ischemia. The results of the study reveal that G-protein-coupled estrogen receptor 1 signaling reduces pro-inflammatory signals and enhances anti-inflammatory signals in the brain at early timepoints after global cerebral ischemia. Furthermore, the study shows that brain-derived estrogen helps to mediate the anti-inflammatory effects of G-protein-coupled estrogen receptor 1 signaling. As a whole, the study demonstrates an important role and synergy of G-protein-coupled estrogen receptor 1 signaling and brain-derived estrogen in the control of early inflammatory events after global cerebral ischemia. An increased understanding of the early-stage regulation of inflammation after global cerebral ischemia could lead to new and improved therapies to protect the brain from ischemic damage and improve outcomes after global cerebral ischemia.AbstractGlobal cerebral ischemia can elicit rapid innate neuroprotective mechanisms that protect against delayed neuronal death. Brain-derived 17β-estradiol (BDE2), an endogenous neuroprotectant, is synthesized from testosterone by the enzyme aromatase (Aro) and is upregulated by brain ischemia and inflammation. Our recent study revealed that G1, a specific G-protein-coupled estrogen receptor 1 (GPER) agonist, exerts anti-inflammatory and anti-apoptotic roles after global cerebral ischemia (GCI). Herein, we aimed to elucidate whether G1 modulates the early inflammatory process and the potential underlying mechanisms in the ovariectomized rat hippocampal CA1 region. G1 was found to markedly reduce pro-inflammatory (iNOS, MHCII, and CD68) and to enhance anti-inflammatory (CD206, Arginase 1, IL1RA, PPARγ, and BDNF) markers after 1 and 3 days of reperfusion after GCI. Intriguingly, the neuroprotection of G1 was blocked by the Aro inhibitor, letrozole. Conversely, the GPER antagonist, G36, inhibited Aro-BDE2 signaling and exacerbated neuronal damage. As a whole, this work demonstrates a novel anti-inflammatory role of GPER, involving a synergistic mediation with BDE2 during the early stage of GCI.Keywords:global cerebral ischemia;G-protein-coupled estrogen receptor 1;aromatase;brain-derived estrogen;inflammation

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