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Neuroprotective Effects of 17-Estradiol and Nonfeminizing Estrogens against H₂O₂ Toxicity in Human Neuroblastoma SK-N-SH Cells

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas (X.W., E.P., R.L., S.Y., J.W.S.); Migenix, Inc., San Diego, California (J.A.D.); and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri (D.F.C.)

Neuroprotective effects of estrogens have been shown in various in vitro and in vivo models, but the mechanisms underlying protection by estrogen are not clear. Mounting evidence suggests antioxidant effects contribute to the neuroprotective effects of estrogens. In the present study, we assessed the protective effects of estrogens against H₂O₂-induced toxicity in human neuroblastoma cells and the potential mechanisms involved in this protection. We demonstrate that 17-estradiol (17-E₂) increases cell survival against H₂O₂ toxicity in human neuroblastoma cells. 17-E₂ effectively reduced lipid peroxidation induced by 5-min H₂O₂ exposure. Furthermore, 17-E₂ exerts the protective effects by maintaining intracellular Ca²⁺ homeostasis, attenuating ATP depletion, ablating mitochondrial calcium overloading, and preserving mitochondrial membrane potential. Two nonfeminizing estrogens, 17- and ent-estradiol, were as effective as 17-E₂ in increasing cell survival, alleviating lipid peroxidation, preserving mitochondrial function, and maintaining intracellular glutathione levels and Ca²⁺ homeostasis against H₂O₂ insult. Moreover, the estrogen receptor antagonist fulvestrant (ICI 182,780) did not block effects of 17-E₂, but increased cell survival and blunted intracellular Ca²⁺ increases. However, these estrogens failed to reduce cytosolic reactive oxygen species, even at concentrations as high as 10 µM. In conclusion, estrogens exert protective effects against oxidative stress by inhibiting lipid peroxidation and subsequently preserving Ca²⁺ homeostasis, mitochondrial membrane potential, and ATP levels.

Address correspondence to: Dr. James W. Simpkins, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107. E-mail: jsimpkin{at}hsc.unt.edu

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