title: Effects of sex steroid hormones and their metabolites on neuronal injury caused by oxygen-glucose deprivation/reoxygenation in organotypic hippocampal slice cultures.
abstract: In this study, protective actions of the sex steroid hormones, progesterone, testosterone, and 17β-estradiol, against oxygen-glucose deprivation (OGD)/reoxygenation-induced neuronal cell death were examined using rat organotypic hippocampal slice cultures. Progesterone, testosterone, and 17β-estradiol significantly attenuated neuronal cell death elicited by OGD/reoxygenation. While the neuroprotection conferred by progesterone was not affected by SU-10603, an inhibitor of cytochrome P45017α, finasteride, a 5α-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone, partially reversed the neuroprotection induced by progesterone. The progesterone metabolite, allopregnanolone attenuated neuronal injury induced by OGD/reoxygenation. Pretreatment with letrozole, a cytochrome P450 aromatase inhibitor or 4-hydroxyphenyl-1-naphthol, a 17β-hydroxysteroid dehydrogenase 2 inhibitor showed no effect on testosterone-mediated neuroprotection, while finasteride completely abolished the protective action of testosterone. Treatment with 5α-dihydrotestosterone significantly suppressed neuronal injury. Pretreatment with mifepristone, a progesterone receptor antagonist and hydroxyflutamid, an androgen receptor antagonist significantly diminished the neuroprotective effects of progesterone and testosterone, respectively. ICI182,780, an estrogen receptor antagonist, showed no effect on neuroprotection mediated by 17β-estradiol. Pretreatment with actinomycin D or cycloheximide clearly abolished the neuroprotective effects of progesterone and testosterone, while actinomycin D and cycloheximide did not show any effect on neuroprotection mediated by 17β-estradiol. Taken together, progesterone protects neurons via progesterone receptor-dependent genomic pathway, and allopregnanolone is involved in progesterone-mediated neuroprotection. Testosterone and its metabolite 5α-dihydrotestosterone protect neurons via the genomic pathway of the androgen receptor. Metabolism of sex steroid hormones in the brain might complicate their protective actions in the brain.
authors.affiliation: Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan. Electronic address: ishiyasu@hiroshima-u.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
authors.affiliation: Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Fujitani
authors.affiliation: Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sakurai
authors.affiliation: Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Takemoto
authors.affiliation: Division of Gene Research, Natural Science Center for Basic Research and Development, Hiroshima University, Higashi-Hiroshima 739-8527, Japan.
authors.forename: Nami
authors.initials: N
authors.lastname: Ikeda-Ishihara
authors.affiliation: Laboratory of Pharmacognosy and Natural Products Chemistry, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan.
authors.forename: Kanami
authors.initials: K
authors.lastname: Mori-Yasumoto
authors.affiliation: Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nehira
authors.affiliation: Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Ishida
authors.affiliation: Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamazaki
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D018696:Neuroprotective Agents; D010100:Oxygen / Q000378:metabolism*; D011280:Pregnanolone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D011944:Receptors, Androgen; D013764:Tetrahydronaphthalenes; D013196:Dihydrotestosterone; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; D018120:Finasteride; C001953:SU 10603; D011280:Pregnanolone; D005947:Glucose; D010100:Oxygen
keywords: 17β-estradiol; Oxygen-glucose deprivation; Progesterone; Steroid metabolism; Testosterone