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Neuronal GPER Participates in Genistein-Mediated Neuroprotection in Ischemic Stroke by Inhibiting NLRP3 Inflammasome Activation in Ovariectomized Female Mice

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Abstract

Estrogen replacement therapy (ERT) is potentially beneficial for the prevention and treatment of postmenopausal cerebral ischemia but inevitably increases the risk of cerebral hemorrhage and breast cancer when used for a long period of time. Genistein, a natural phytoestrogen, has been reported to contribute to the recovery of postmenopausal ischemic stroke with reduced risks. However, the underlying mechanism of genistein-mediated neuroprotection remains unclear. We reported that genistein exerted significant neuroprotective effects by enhancing the expression of neuronal G protein-coupled estrogen receptor (GPER) in the ischemic penumbra after cerebral reperfusion in ovariectomized (OVX) mice, and this effect was achieved through GPER-mediated inhibition of nod-like receptor protein 3 (NLRP3) inflammasome activation. In addition, we found that peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) was the pivotal molecule that participated in GPER-mediated inhibition of NLRP3 inflammasome activation in OVX mice after ischemia/reperfusion (I/R) injury. Our data suggest that the neuronal GPER/PGC-1α pathway plays an important role in genistein-mediated neuroprotection against I/R injury in OVX mice.

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Data Availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

ERT:

Estrogen replacement therapy

GPER:

G protein-coupled estrogen receptor

OVX:

Ovariectomized

NLRP3:

Nod-like receptor protein 3

PGC-1α:

Peroxisome proliferator-activated receptor-gamma coactivator 1α

Genistein:

4′,5,7-Trihydroxyisoflavone

I/R:

Ischemia/reperfusion

MCAO:

Middle cerebral artery occlusion

TTC:

2,3,5-Triphenyltetrazolium chloride

PFA:

Paraformaldehyde

PBS:

Phosphate-buffered saline

TUNEL:

Terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick-end labeling

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

RT-qPCR:

Quantitative reverse transcription polymerase chain reaction

PLA:

Proximity ligation assay

ASC:

Apoptosis-associated speck-like protein

BBB:

Blood-brain barrier

LPS:

Lipopolysaccharide

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Funding

This work was supported by the National Natural Science Foundation of China (no. 81971226 to WGH; no. 81901079 to HYG), the Shaanxi Provincial Natural Science Foundation for Distinguished Young Scholars (no. 2021JC-33 to WGH), and the Surface Project of Shaanxi Provincial Natural Science Foundation (no. 2030JM-330 to SQW).

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Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710032, China

    Shiquan Wang, Zhen Zhang, Jin Wang, Lina Ma, Jianshuai Zhao, Jiajia Wang, Zongping Fang, Wugang Hou & Haiyun Guo

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Contributions

H.G. and W.H. conceived and designed the study. S.W., Z.Z., J.W., L.M., J.Z., J.W., and Z.F. performed the experiments and data analysis. S.W., Z.Z., and J.W. prepared figures and the manuscript draft. H.G. wrote the paper. All authors read and approved the final manuscript.

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Correspondence to Wugang Hou or Haiyun Guo.

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Shiquan Wang, Zhen Zhang, and Jin Wang contributed equally to this article.

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Wang, S., Zhang, Z., Wang, J. et al. Neuronal GPER Participates in Genistein-Mediated Neuroprotection in Ischemic Stroke by Inhibiting NLRP3 Inflammasome Activation in Ovariectomized Female Mice. Mol Neurobiol 59, 5024–5040 (2022). https://doi.org/10.1007/s12035-022-02894-4

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