The Functional Study Of A New Class Of Selective Estrogen Receptor Modulators With Oxabicyclic[2.2.1]Heptene Core

Alzheimer's disease(AD)is a aging neurodegenerative disease.Its hallmark characteristic is the deposition of amyloid beta(A?)in the brain.Epidemiological studies indicate that estrogen replacement therapy(ERT)can improve or maintain levels of cognitive function in postmenopausal women and reduce the risk of developing AD.ERT,however,increased the risks of breast cancer and endometrial cancer.Because of their tissue selectivity,selective estrogen receptor modulators(SERMs)are a safer therapeutic alternative for treating AD.Oxabicycloheptene sulfonate(OBHS)is a novel bicyclic core selective estrogen receptor modulator(SERM)with estrogen receptor(ER)antagonistic-activity and anti-inflammatory activity,which is similar to raloixfene(RAL).Thus,we speculated that OBHS may exhibit similar protective effect to that of RAL.In the present study,OBHS demonstrated a remarkably protective effect against amyloid beta(A?)induced cytotoxicity via G-protein-coupled estrogen receptor 1(GPER1)in rat astroglial cell line(C6).The C6 cell death induced by A? was decreased by OBHS(1 p,M)treatment for 45 minutes.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 formed a hydrogen bond on extracellular loop(EC)3 of GPER1,which is,in turn,linked to GPERl's agonist properties,according to the molecular docking analysis.Collectively,these data showed that OBHS has potent agonistic effects on GPER1 in C6 astroglial cells.We speculated that OBHS may have antioxidant activity,since it bears a "A ring"mimic of natural estrogens.In our study,OBHS increased Bcl-2 protein levels and had a significant protective effect against H2O2-induced injury in C6 cells.Additionally,OBHS decreased the proliferation of MCF-7(breast cancer cells),SK-OV-3(ovarian cancer cells)and DU145(prostate cancer cells).And OBHS had greater in vitro therapeutic index(IVTI)than that of RAL for breast cancer.It was implicated that OBHS is a safer compound.In summary,this is the first report to characterize OBHS as an agonist of GPER1 with low side effects and antioxidant activity that exerts rapid protective action in C6 astroglial cells.Our in vitro study demonstrated that OBHS protected astrocytes from A?-induced toxicity and up-regulated Bcl-2 protein levels by activation of GPER1-PI3K/Akt and ERK signaling pathways.And,OBHS might contain a protective pharmacophore targeting GPER1 activity and ER-antagonistic activity.These observations suggest OBHS as a potential drug for AD by virtue of its estrogen receptors' selectivity,which grants it as a promising alternative for hormone replacement therapy.