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

Global 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 inflamma...

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Published in:Biology (Basel, Switzerland) Switzerland), 2023-01, Vol.12 (1), p.99
Main Authors: Xu, Jing, Bai, Jing, Gao, Fujia, Xu, Chao, Huang, Yuanyuan, Li, Danyang, Wang, Lu, Wang, Ruimin
Format: Article
Language:English
Subjects:
17β-Estradiol
Animals
Apoptosis
Arginase
Aromatase
Brain injury
brain-derived estrogen
Brain-derived neurotrophic factor
Carotid arteries
Cytokines
Estrogen receptors
Estrogens
G-protein-coupled estrogen receptor 1
Genotype & phenotype
global cerebral ischemia
Hippocampus
Inflammation
Interleukin 1 receptor antagonist
Ischemia
Neuroprotection
Neuroprotective agents
Nitric-oxide synthase
Ovariectomy
Reperfusion
Testosterone
Traumatic brain injury
Veins & arteries
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Summary:Global 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.
ISSN:2079-7737
2079-7737
DOI:10.3390/biology12010099