Neuroprotection with non-feminizing estrogen analogues: An overlooked possible therapeutic strategy

This article is part of a Special Issue "Hormones & Neurotrauma".Although many of the effects of estrogens on the brain are mediated through estrogen receptors (ERs), there is evidence that neuroprotective activity of estrogens can be mediated by non-ER mechanisms. Herein, we review the substantial evidence that estrogens neuroprotection is in large part non-ER mediated and describe in vitro and in vivo studies that support this conclusion. Also, we described our drug discovery strategy for capitalizing on enhancement in neuroprotection while at the same time, reducing ER binding of a group of synthetic non-feminizing estrogens. Finally, we offer evidence that part of the neuroprotection of these non-feminizing estrogens is due to enhancement in redox potential of the synthesized compounds.

► Estrogens have been shown to have an intrinsic antioxidant structure that lies in the phenolic ring of the compounds.
► We and others have determined that the phenolic nature of the estradiol molecule is essential for neuroprotection.
► Synthetically increasing the redox potential of the phenoxy radical provides better neuroprotective properties.
► We have shown that estrogen-like compounds can protect an in vitro Friedreich's Ataxia cell model against oxidative stress.
► Estradiol administration attenuates infarct volume and is neuroprotective in experimental animal models of cerebral ischemia.