title: Estrogen protection in Friedreich's ataxia skin fibroblasts.
abstract: Estrogens have been shown to have protective effects on a wide range of cell types and animal models for many neurodegenerative diseases. The present study demonstrates the cytoprotective effects of 17β-estradiol (E2) and estrogen-like compounds in an in vitro model of Friedreich's ataxia (FRDA) using human donor FRDA skin fibroblasts. FRDA fibroblasts are extremely sensitive to free radical damage and oxidative stress, produced here using l-buthionine (S,R)-sulfoximine to inhibit de novo glutathione synthesis. We have shown that the protective effect of E2 in the face of l-buthionine (S,R)-sulfoximine -induced oxidative stress is independent of estrogen receptor-α, estrogen receptor-β or G protein-coupled receptor 30 as shown by the inability of either ICI 182,780 or G15 to inhibit the E2-mediated protection. These cytoprotective effects appear to be dependent on antioxidant properties and the phenolic structure of estradiol as demonstrated by the observation that all phenolic compounds tested were protective, whereas all nonphenolic compounds were inactive, and the observation that the phenolic compounds reduced the levels of reactive oxygen species, whereas the nonphenolic compounds did not. These data show for the first time that phenolic E2-like compounds are potent protectors against oxidative stress-induced cell death in FRDA fibroblasts and are possible candidate drugs for the treatment and prevention of FRDA symptoms.
authors.affiliation: Institute for Aging and Alzheimer’s Disease Research, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA. james.simpkins@unthsc.edu
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Richardson
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Yang
authors.forename: Yi
authors.initials: Y
authors.lastname: Wen
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D005978:Glutathione / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D020847:Estrogen Receptor Modulators; D004967:Estrogens; C109584:GPER1 protein, human; D018696:Neuroprotective Agents; D010636:Phenols; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol; D019328:Buthionine Sulfoximine; D005978:Glutathione