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Oxabicycloheptene Sulfonate Protects Against β-Amyloid-induced Toxicity by Activation of PI3K/Akt and ERK Signaling Pathways Via GPER1 in C6 Cells

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Abstract

Oxabicycloheptene sulfonate (OBHS) is a novel bicyclic core selective estrogen receptor modulator (SERM) with estrogen receptor (ER) antagonistic-activity and anti-inflammatory activity. However, little is known about protective action of OBHS on neurodegenerative disorders. In the present study, OBHS demonstrated a remarkably protective effect against amyloid beta (Aβ) induced cytotoxicity via G-protein-coupled estrogen receptor 1 (GPER1) in rat astroglial cell line (C6). The C6 cell death induced by Aβ was decreased by OBHS (1 μM) treatment for 45 min. This rapid protective action was blocked by GPER1 specific antagonist or siRNA knockdown. Inhibitors of phosphatidylinositol 3-kinase (PI3k)/Akt and extracellular signal-regulated kinase (ERK) activation also exhibited similar effects as GPER1 antagonist in blocking the protective effects of OBHS. Moreover, the expression of anti-apoptotic protein Bcl-2 was also increased by OBHS as a consequence of the activation of GPER1-PI3K/Akt and ERK pathways. Additionally, the phenyl sulfonate moiety of OBHS played a vital role in producing GPER1’s agonist property according to the molecular docking analysis. These findings suggest that OBHS provide protection directed at enhancing glial cell survival through the activation of GPER1, which, in turn, offers a novel insight into the molecular mechanisms behind the potential application of OBHS in treating Alzheimer’s disease (AD).

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid beta

ERT:

Estrogen replacement therapy

GPER1:

G-Protein-coupled estrogen receptor 1

ERs:

Estrogen receptors

CNS:

Central nervous system

PI3K:

Phosphatidylinositol 3-kinase

ERK:

Extracellular signal regulated kinase

DMEM:

Dulbecco’s modified Eagle’s medium

OBHS:

Oxabicycloheptene sulfonate

RAL:

Raloxifene

SERMs:

Selective estrogen receptor modulators

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31371331, 81573279, 81373255) and the National Basic Research Program of China (973 Program) (2012CB720600) and Hubei Province’s Outstanding Medical Academic Leader Program. We thank Dr. Liu-Qing Yang in Johns Hopkins University School of Medicine for writing assistance.

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Authors and Affiliations

  1. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, People’s Republic of China

    Li-Juan Deng, Chen Cheng, Jun Wu & Jian Huang

  2. Computer School of Wuhan University, Wuhan, Hubei, 430072, People’s Republic of China

    Cai-Hua Wang

  3. State Key Laboratory of Virology, Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, People’s Republic of China

    Hai-Bing Zhou

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  1. Li-Juan Deng
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Deng, LJ., Cheng, C., Wu, J. et al. Oxabicycloheptene Sulfonate Protects Against β-Amyloid-induced Toxicity by Activation of PI3K/Akt and ERK Signaling Pathways Via GPER1 in C6 Cells. Neurochem Res 42, 2246–2256 (2017). https://doi.org/10.1007/s11064-017-2237-5

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