The nonfeminizing enantiomer of 17 beta-estradiol exerts protective effects in neuronal cultures and a rat model of cerebral ischemia

Estrogens are potent neuroprotective compounds in a variety of animal and c ell culture models, and data indicate that estrogen receptor (ER)-mediated gene transcription is not required for some of these effects. To further ad dress the requirement for an ER in estrogen enhancement of neuronal surviva l, we assessed the enantiomer of 17 beta -estradiol (Ent-E-2), which has id entical chemical properties but interacts only weakly with known ERs, for n europrotective efficacy. Ent-E-2 was both as potent and efficacious as 17 b eta -estradiol in attenuating oxidative stress-induced death in HT-22 cells , a murine hippocampal cell line. Further, Ent-E-2 completely attenuated H2 O2 toxicity in human SK-N-SH neuroblastoma cells at a 10 nM concentration. In a rodent model of focal ischemia, 17 beta -estradiol (100 mug/kg) or Ent -E-2 (100 mug/kg), injected 2 h before middle cerebral artery occlusion, re sulted in a 60 and 61% reduction in lesion volume, respectively. Ent-E-2, a t the doses effective in this study, did not stimulate uterine growth or va ginal opening in juvenile female rats when administered daily for 3 days. T hese data indicate that the neuroprotective effects of estrogens, both in v itro and in vivo, can he disassociated from the peripheral estrogenic actio ns.