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The Nonfeminizing Enantiomer of 17ß-Estradiol Exerts Protective Effects in Neuronal Cultures and a Rat Model of Cerebral Ischemia¹

Center for the Neurobiology of Aging (P.S.G., S.-H.Y., J.W.S.), Department of Pharmacodynamics (J.W.S.), and Department of Neurosurgery (S.-H.Y.), University of Florida, Gainesville, Florida 32610; and Department of Molecular Biology and Pharmacology (K.R.N., A.S.K., D.F.C.), Washington University, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Pattie S. Green, 629 South Elm Street, Slot 807, Donald W. Reynolds Center on Aging, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205. E-mail: greenpatties{at}uams.edu

Estrogens are potent neuroprotective compounds in a variety of animal and cell culture models, and data indicate that estrogen receptor (ER)-mediated gene transcription is not required for some of these effects. To further address the requirement for an ER in estrogen enhancement of neuronal survival, we assessed the enantiomer of 17ß-estradiol (Ent-E₂), which has identical chemical properties but interacts only weakly with known ERs, for neuroprotective efficacy. Ent-E₂ was both as potent and efficacious as 17ß-estradiol in attenuating oxidative stress-induced death in HT-22 cells, a murine hippocampal cell line. Further, Ent-E₂ completely attenuated H₂O₂ toxicity in human SK-N-SH neuroblastoma cells at a 10 nM concentration. In a rodent model of focal ischemia, 17ß-estradiol (100 µg/kg) or Ent-E₂ (100 µg/kg), injected 2 h before middle cerebral artery occlusion, resulted in a 60 and 61% reduction in lesion volume, respectively. Ent-E₂, at the doses effective in this study, did not stimulate uterine growth or vaginal opening in juvenile female rats when administered daily for 3 days. These data indicate that the neuroprotective effects of estrogens, both in vitro and in vivo, can be disassociated from the peripheral estrogenic actions.

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