title: Estradiol protects mesencephalic dopaminergic neurons from oxidative stress-induced neuronal death.
abstract: Oxidative stress is important in the process of dopaminergic neuronal degeneration in Parkinson's disease. Recent studies suggest that estrogens have neuroprotective effects in neurodegenerative disorders, including Alzheimer's disease. In the present study, we investigated neuroprotection against oxidative stress afforded by estradiol using primary neuronal culture of the rat ventral mesencephalon. Oxidative stress induced by glutamate, superoxide anions, and hydrogen peroxide caused significant neuronal death. Although simultaneous administration of 17beta-estradiol and glutamate did not show any significant effects, preincubation with 17beta-estradiol provided significant neuroprotection against glutamate-induced neurotoxicity (ED50 was 50 microM for dopaminergic and 15 microM for nondopaminergic neurons). Neuroprotection occurred even after a brief preincubation with 17beta-estradiol and was not significantly blocked by either an estrogen receptor antagonist or a protein synthesis inhibitor. These findings indicate that the neuroprotection against glutamate neurotoxicity is mediated by neither estrogen receptors nor activation of genome transcription. Other steroids (corticosterone, testosterone, and cholesterol) did not provide significant neuroprotection against glutamate-induced neurotoxicity. Furthermore, preincubation with 17beta-estradiol provided neuroprotection against neuronal death induced by both superoxide anions and hydrogen peroxide. Dichlorofluorescin diacetate, a marker of oxygen radicals, revealed that preincubation with 17beta-estradiol suppressed intracellular oxygen radicals induced by hydrogen peroxide. The biologically inactive stereoisomer of estradiol, 17alpha-estradiol, provided neuroprotection against glutamate-induced toxicity in dopaminergic neurons, as well as the 17beta isoform. 17Alpha-estradiol may be a potential therapeutic agent used to prevent dopaminergic neuronal death induced by oxidative stress in Parkinson's disease.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sawada
authors.forename: M
authors.initials: M
authors.lastname: Ibi
authors.forename: T
authors.initials: T
authors.lastname: Kihara
authors.forename: M
authors.initials: M
authors.lastname: Urushitani
authors.forename: A
authors.initials: A
authors.lastname: Akaike
authors.forename: S
authors.initials: S
authors.lastname: Shimohama
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology*; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017382:Reactive Oxygen Species; D013237:Stereoisomerism; D013481:Superoxides / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D013739:Testosterone / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013629:Tamoxifen; D013481:Superoxides; D018698:Glutamic Acid; D013739:Testosterone; D004958:Estradiol; D006861:Hydrogen Peroxide; D004298:Dopamine; D003345:Corticosterone