TY - JOUR T1 - A Nonfeminizing Estrogen Analog Protects against Ethanol Withdrawal Toxicity in Immortalized Hippocampal Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 543 LP - 550 DO - 10.1124/jpet.106.103630 VL - 319 IS - 2 AU - Marianna E. Jung AU - Andrew M. Wilson AU - James W. Simpkins Y1 - 2006/11/01 UR - http://jpet.aspetjournals.org/content/319/2/543.abstract N2 - We have shown that 17β-estradiol protects against ethanol withdrawal toxicity in rats. Here, we investigated whether a cellular model of ethanol withdrawal could be developed in a cultured hippocampal cell line (HT22) and whether an adamantyl-containing nonfeminizing estrogen analog, ZYC26 [(3-hydroxy-2-adamantyl(1)-4-methyl-estra-1,3,5(10)-17-one], protects against ethanol withdrawal toxicity. HT22 cells were exposed to ethanol (0–500 mM) for 24 h in the presence or absence of ZYC26 or 17β-estradiol. The ethanol solution was then removed from the cells for 4 h to create ethanol withdrawal. Samples were collected at the end of a 24-h ethanol exposure or at 4 h of ethanol withdrawal to assess cell viability using a calcein assay, lipid peroxidation by measuring malondialdehyde, and protein oxidation by measuring carbonyl contents. When tested, ethanol concentrations were constantly maintained during a 24-h ethanol exposure and eliminated at 4 h of ethanol withdrawal. Ethanol withdrawal decreased cell viability and increased the levels of malondialdehyde and carbonyls more than ethanol exposure. ZYC26 reduced the cell death and malondialdehyde levels at a lower dose (1 μM) than 17β-estradiol (10 μM). The increased carbonyl contents were reduced only by ZYC26 treatment. These data suggest that ethanol withdrawal can be created in HT22 cells in a manner that is more toxic than ethanol exposure and that ZYC26 is a more potent cytoprotectant than 17β-estradiol against cell death and oxidative damage induced by ethanol withdrawal. Therefore, ZYC26 can be a potential alternative estrogen therapy for a cellular and oxidative imbalance associated with ethanol withdrawal. The American Society for Pharmacology and Experimental Therapeutics ER -