G-protein-coupled estrogen receptor 1(GPER1)has been implicated in neuroprotection of selective estrogen receptor modulators(SERMs)against various insults in the brain.However,the cellular mechanisms of SERMs interaction with GPER1 is not well documented.In present study,raloxifene(RAL)and oxabicycloheptene sulfonate(OBHS),demonstrated a remarkably protective effect against amyloid beta(Aβ)induced cytotoxicity via GPER1 in rat astroglial cell line(C6).The C6 cell death induced by Aβ was decreased by RAL(1 μM)or OBHS(1 μ M)treatment for 45 minutes.The rapid protective actions were blocked by GPER1 specific antagonist or siRNA knockdown.Inhibitors of phosphatidylinositol 3-kinase(PI3k)/Akt and extracellular signal-regulated kinase(ERK)activation exhibited similar effect as GPER1 antagonist in blocking the pro-survival effect of RAL/OBHS.Moreover,the expression of anti-apoptotic protein Bcl-2 was also increased by RAL/OBHS as a consequence of GPER1-PI3K/Akt and ERK pathways activation.These findings suggest that RAL and OBHS provide neuroprotection directed at enhancing glial cell survival through the activation of GPER1,which offers a novel molecular insight into the potential application of RAL and OBHS for Alzheimers disease(AD).