Neuroprotective properties of selective estrogen receptor agonists in cultured neurons.

To investigate the role of the estrogen receptor (ER) in mediating neuroprotection, the neuroprotective profiles of selective ER agonists for ERalpha and ERbeta, propylpyrazole triol (PPT) and 2,3-bis(4-hydroxyphenyl) proprionitrile (DPN), respectively, were compared to that of 17beta-estradiol and 17alpha-estradiol in primary neuron cultures challenged by beta-amyloid toxicity. All compounds were found to be neuroprotective in an ER-dependent manner. However, protein kinase C (PKC) inhibition completely blocked the protective effects of 17beta-estradiol and 17alpha-estradiol and significantly attenuated PPT but not DPN neuroprotection. These data indicate that estrogen-mediated neuroprotection likely involves a variety of mechanisms and that protection due to PKC activation is more likely due to ERalpha compared to ERbeta.