title: Allopregnanolone-mediated protective effects of progesterone on tributyltin-induced neuronal injury in rat hippocampal slices.
abstract: Increasing evidence shows that progesterone, a neuroactive steroid, has protective actions in central nervous system, but there is little evidence to show the protective mechanism of progesterone on neurotoxicity induced by environmental chemicals. In this study, we examined the effects of progesterone on neuronal injury induced by tributyltin (TBT) in rat hippocampal slices. Treatment with progesterone dose-dependently suppressed hippocampal neuronal injury induced by TBT. The neuroprotective action of progesterone was completely canceled with pretreatment by finasteride, a 5α-reductase inhibitor, but it was not affected by mifepristone, a progesterone receptor antagonist, or by SU-10603, a cytochrome P450 17α inhibitor. The content of allopregnanolone in the slices was significantly increased by treatment with progesterone, and this increment was greatly suppressed with a pretreatment of finasteride. Treatment with allopregnanolone attenuated neuronal injury induced by TBT in a dose-dependent manner. The neuroprotective effects not only of progesterone but also of allopregnanolone were canceled by bicuculline, a potent gamma-aminobutyric acid A (GABAA) receptor antagonist. Pretreatment with muscimol, a GABAA receptor agonist, attenuated hippocampal neuronal injury elicited by TBT. Taken together, allopregnanolone converted from progesterone in hippocampal slices could protect neurons from TBT-induced neurotoxicity due to a GABAA receptor-dependent mechanism. One of the physiological roles of neuroactive steroids might be neuroprotection from environmental chemicals.
authors.affiliation: Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Tomohito
authors.initials: T
authors.lastname: Kawami
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Ishida
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamazaki
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D018120:Finasteride / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects*; D006727:Hormone Antagonists / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011280:Pregnanolone / Q000378:metabolism / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013764:Tetrahydronaphthalenes; D014220:Trialkyltin Compounds / Q000633:toxicity
chemical_list: D058891:5-alpha Reductase Inhibitors; D000777:Anesthetics; D065607:Cytochrome P-450 Enzyme Inhibitors; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006727:Hormone Antagonists; D018696:Neuroprotective Agents; D011372:Progestins; D013764:Tetrahydronaphthalenes; D014220:Trialkyltin Compounds; D009118:Muscimol; D015735:Mifepristone; D011374:Progesterone; C011559:tributyltin; D018120:Finasteride; C001953:SU 10603; D011280:Pregnanolone; D001640:Bicuculline