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The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties.

Among the family of steroidal molecules, only estrogens have the capability of preventing neuronal cell death caused by increased oxidative burden. Employing neuronal cell lines, brain membrane, and low density lipoprotein oxidation assays, we show that the antioxidant and neuroprotective effects of estrogens are dependent not on their genomic properties as hormones but rather on their basic chemical properties as hydrophobic phenolic molecules. Concentrations of 17beta-estradiol of 0.1-500 nM, which confer maximum estrogen receptor-dependent gene transcription in vitro as well as maximum estrogen receptor binding, respectively, do not show antioxidant or neuroprotective effects. In contrast, phenolic compounds such as 2,4,6-trimethylphenol, N-acetylserotonin, and 5-hydroxyindole exhibit neuroprotective effects without any estrogenicity. Comparing various natural and synthetic mono- and polyphenolic compounds, no correlation between their antioxidant cytoprotective effect and their estrogenic potency can be seen. These results call into question the idea of a general correlation between the intended pharmacological effects of estrogens and phenolic compounds and their effect on estrogen receptor-dependent pathways. Furthermore, they may open the door toward the rational design of neuroprotective antioxidants with decreased hormonal side effects.