title: Investigation of the mechanisms of progesterone protection following oxygen-glucose deprivation in organotypic hippocampal slice cultures.
abstract: This study aimed to test the hypothesis that progesterone is neuroprotective against oxygen-glucose deprivation (OGD) through its conversion to the active metabolite allopregnanolone (AlloP) and the potentiation of GABA(A) receptors. Organotypic hippocampal cultures were exposed to 2h of OGD and the resulting cell death was quantified 24h later using combined propidium iodide and Hoechst immunostaining. Initially, we confirmed, that both progesterone and AlloP were protective in terms of reducing cell death following OGD in hippocampal cultures and for both, the optimal level of protection was observed at a concentration of 0.1μM. However, the protective effect of progesterone was absent in the presence of finasteride (10μM) which inhibits the metabolism of progesterone to active metabolites, including AlloP. In addition, the concurrent application of picrotoxin (100μM), a potent GABA(A) receptor antagonist, prevented the protection previously seen by either progesterone or AlloP alone. These results indicate that progesterone protects hippocampal cultures from cell death following OGD largely due to its conversion to AlloP and that GABA(A) receptors are important mediators of the protective effects of both progesterone and AlloP.
authors.affiliation: School of Psychology, University of Leicester, Leicester, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Radley
authors.forename: Asha
authors.initials: A
authors.lastname: Akram
authors.forename: Blair D
authors.initials: BD
authors.lastname: Grubb
authors.forename: Claire L
authors.initials: CL
authors.lastname: Gibson
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018120:Finasteride / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D000860:Hypoxia / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010852:Picrotoxin / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology*; D011419:Propidium
chemical_list: D058891:5-alpha Reductase Inhibitors; D018120:Finasteride; D018756:GABA Antagonists; D005947:Glucose; D018696:Neuroprotective Agents; D010852:Picrotoxin; D011280:Pregnanolone; D011374:Progesterone; D011419:Propidium