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

Overview

Journal Neurochem Res

Specialties Chemistry
Neurology

Date 2017 Apr 5

PMID 28374135

Citations 4

Authors

Li-Juan Deng

Chen Cheng

Jun Wu

Cai-Hua Wang

Hai-Bing Zhou

Jian Huang

Affiliations

Soon will be listed here.

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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References

Costanzi S . Homology modeling of class a G protein-coupled receptors. Methods Mol Biol. 2012; 857:259-79. PMC: 3354613. DOI: 10.1007/978-1-61779-588-6_11. View

Henderson V . Alzheimer's disease: review of hormone therapy trials and implications for treatment and prevention after menopause. J Steroid Biochem Mol Biol. 2013; 142:99-106. PMC: 3830600. DOI: 10.1016/j.jsbmb.2013.05.010. View

Hu X, Yuan Y, Wang D, Su Z . Heterogeneous astrocytes: Active players in CNS. Brain Res Bull. 2016; 125:1-18. DOI: 10.1016/j.brainresbull.2016.03.017. View

ONeill K, Chen S, Brinton R . Impact of the selective estrogen receptor modulator, raloxifene, on neuronal survival and outgrowth following toxic insults associated with aging and Alzheimer's disease. Exp Neurol. 2003; 185(1):63-80. DOI: 10.1016/j.expneurol.2003.09.005. View

Shi C, Zheng D, Fang L, Wu F, Kwong W, Xu J . Ginsenoside Rg1 promotes nonamyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK and PI3K/Akt. Biochim Biophys Acta. 2011; 1820(4):453-60. DOI: 10.1016/j.bbagen.2011.12.005. View

Tang H, Zhang Q, Yang L, Dong Y, Khan M, Yang F . GPR30 mediates estrogen rapid signaling and neuroprotection. Mol Cell Endocrinol. 2014; 387(1-2):52-8. PMC: 4019970. DOI: 10.1016/j.mce.2014.01.024. View

Wang G, Dinkins M, He Q, Zhu G, Poirier C, Campbell A . Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD). J Biol Chem. 2012; 287(25):21384-95. PMC: 3375560. DOI: 10.1074/jbc.M112.340513. View

Bourque M, Morissette M, Cote M, Soulet D, Di Paolo T . Implication of GPER1 in neuroprotection in a mouse model of Parkinson's disease. Neurobiol Aging. 2012; 34(3):887-901. DOI: 10.1016/j.neurobiolaging.2012.05.022. View

Stragier E, Martin V, Davenas E, Poilbout C, Mongeau R, Corradetti R . Brain plasticity and cognitive functions after ethanol consumption in C57BL/6J mice. Transl Psychiatry. 2015; 5:e696. PMC: 5068583. DOI: 10.1038/tp.2015.183. View

10.

Quincozes-Santos A, Bobermin L, Latini A, Wajner M, Souza D, Goncalves C . Resveratrol protects C6 astrocyte cell line against hydrogen peroxide-induced oxidative stress through heme oxygenase 1. PLoS One. 2013; 8(5):e64372. PMC: 3654976. DOI: 10.1371/journal.pone.0064372. View

11.

Prossnitz E, Barton M . The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol. 2011; 7(12):715-26. PMC: 3474542. DOI: 10.1038/nrendo.2011.122. View

12.

DonCarlos L, Azcoitia I, Garcia-Segura L . Neuroprotective actions of selective estrogen receptor modulators. Psychoneuroendocrinology. 2009; 34 Suppl 1:S113-22. PMC: 2794899. DOI: 10.1016/j.psyneuen.2009.04.012. View

13.

Hazell G, Yao S, Roper J, Prossnitz E, OCarroll A, Lolait S . Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. J Endocrinol. 2009; 202(2):223-36. PMC: 2710976. DOI: 10.1677/JOE-09-0066. View

14.

Karki P, Webb A, Zerguine A, Choi J, Son D, Lee E . Mechanism of raloxifene-induced upregulation of glutamate transporters in rat primary astrocytes. Glia. 2014; 62(8):1270-83. PMC: 4061260. DOI: 10.1002/glia.22679. View

15.

Lee K, Koh S, Noh M, Kim S, Lee Y . Phosphatidylinositol-3-kinase activation blocks amyloid beta-induced neurotoxicity. Toxicology. 2007; 243(1-2):43-50. DOI: 10.1016/j.tox.2007.09.020. View

16.

Kajta M, Rzemieniec J, Litwa E, Lason W, Lenartowicz M, Krzeptowski W . The key involvement of estrogen receptor β and G-protein-coupled receptor 30 in the neuroprotective action of daidzein. Neuroscience. 2013; 238:345-60. DOI: 10.1016/j.neuroscience.2013.02.005. View

17.

Vargas M, Johnson J . The Nrf2-ARE cytoprotective pathway in astrocytes. Expert Rev Mol Med. 2009; 11:e17. PMC: 5563256. DOI: 10.1017/S1462399409001094. View

18.

Rossouw J, Prentice R, Manson J, Wu L, Barad D, Barnabei V . Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007; 297(13):1465-77. DOI: 10.1001/jama.297.13.1465. View

19.

Nwachukwu J, Srinivasan S, Zheng Y, Wang S, Min J, Dong C . Predictive features of ligand-specific signaling through the estrogen receptor. Mol Syst Biol. 2016; 12(4):864. PMC: 4848761. DOI: 10.15252/msb.20156701. View

20.

Bhattacharya S, Hall S, Li H, Vaidehi N . Ligand-stabilized conformational states of human beta(2) adrenergic receptor: insight into G-protein-coupled receptor activation. Biophys J. 2007; 94(6):2027-42. PMC: 2257890. DOI: 10.1529/biophysj.107.117648. View