Roles of estrogen receptors alpha and beta in sexually dimorphic neuroprotection against glutamate toxicity

Although most agree that 17β-estradiol is neuroprotective via a variety of mechanisms, less is known about the role that biological sex plays in receptor-mediated estradiol neuroprotection. To address this issue we isolated primary cortical neurons from rat pups sorted by sex and assessed the ability of estradiol to protect the neurons from death induced by glutamate. Five-minute pretreatment with 10-50 nM 17β-estradiol protected female but not male neurons from glutamate toxicity 24 h later. Both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) are expressed in these cultures. Experiments using an ERα selective agonist or antagonist indicate that this receptor is important for neuroprotection in female cortical neurons. The ERβ selective agonist conveys a small degree of neuroprotection to both male and female cortical neurons. Interestingly, we found that 17α estradiol and the novel membrane estrogen receptor (mER) agonist STX, but not bovine serum albumin conjugated estradiol or the GPR30 agonist G1 were neuroprotective in both male and female neurons. Taken together these data highlight a role for ERα in sexually dimorphic neuroprotection.