Estrogen receptor (ER)-aα36 is involved in estrogen- and tamoxifen-induced neuroprotective effects in ischemic stroke models

Abstract

The neuroprotection by estrogen (E2) and tamoxifen is well documented in experimental stroke models; however, the exact mechanism is unclear. A membrane-based estrogen receptor, ER-aα36, has been identified. Postmenopausal-levels of E2 act through ER-aα36 to induce osteoclast apoptosis due to a prolonged activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) signaling. We hypothesized that ER-aα36 may play a role in the neuroprotective activities of estrogen and tamoxifen. Here, we studied ER-aα36 expression in the brain, as well as its neuroprotective effects against oxygen and glucose deprivation (OGD) in PC12 cells. We found that ER-aα36 was expressed in both rat and human brain. In addition, OGD-induced cell death was prevented by l nmol/L 17β-estradiol (E2β). E2β activates the MAPK/ERK signaling pathway in PC12 cells under basal and OGD conditions by interacting with ER-aα36 and also induces ER-aα36 expression. Low-dose of tamoxifen up-regulated ER-aα36 expression and enhanced neuronal survival in an ovariectomized ischemic stroke model. Furthermore, low-dose of tamoxifen enhanced neuroprotective effects by modulating activates or suppress ER-aα36. Our results thus demonstrated that ER-aα36 is involved in neuroprotective activities mediated by both estrogen and tamoxifen. Copyright: