title: Allopregnanolone protects against dopamine-induced striatal damage after in vitro ischaemia via interaction at GABA A receptors.
abstract: Sex steroid hormones, such as progesterone, have been shown to display neuroprotective properties after various models of central nervous system injury, including cerebral ischaemia, although the mechanism(s) of action remain largely undetermined. Allopregnanolone, an active progesterone metabolite, may explain some of the protective actions of progesterone. We utilised an in vitro model of ischaemia to evaluate the neuroprotective potential of allopregnanolone and examine its interaction at the GABA(A)  receptor, which is hypothesised to be its main neuroprotective mechanism. In adult male mouse coronal caudate slices exposed to oxygen glucose deprivation (OGD), we measured aspects of OGD-induced dopamine release, which is neurotoxic during ischaemia, using fast cyclic voltammetry and also assessed tissue viability. The GABA(A)  agonist, muscimol, displayed a neuroprotective profile in terms of delaying the OGD-evoked dopamine efflux (P < 0.05) and reducing the amount of dopamine released after OGD (P < 0.05). Allopregnanolone, at a concentration of 10(-6)  m, also displayed a neuroprotective profile because it significantly reduced the amount of dopamine efflux (P < 0.05) and reduced the loss of viable tissue after OGD compared to slices exposed to vehicle during OGD (P < 0.05). However, the effect of 10(-6)  m allopregnanolone on dopamine efflux was prevented in the presence of bicuculline, a competitive GABA(A)  receptor antagonist. These results describe the use of an in vitro model of ischaemia with respect to determining that allopregnanolone is neuroprotective during the acute phase of ischaemia, and also demonstrate that such actions are dependent, at least in part, upon interaction at the GABA(A)  receptor.
authors.affiliation: School of Psychology, University of Leicester, Leicester, UK.
authors.forename: S R
authors.initials: SR
authors.lastname: Knight
authors.forename: C
authors.initials: C
authors.lastname: Davidson
authors.forename: A M J
authors.initials: AM
authors.lastname: Young
authors.forename: C L
authors.initials: CL
authors.lastname: Gibson
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity*; D018755:GABA Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D011280:Pregnanolone / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018755:GABA Agonists; D011963:Receptors, GABA-A; D011280:Pregnanolone; D004298:Dopamine