title: Neuroactive steroids induce changes in fetal sheep behavior during normoxic and asphyxic states.
abstract: Allopregnanolone and related steroids are potent γ-aminobutyric acid receptor-A receptor agonistic allosteric modulators that suppress central nervous system (CNS) activity; in some species, these neurosteroids regulate normal CNS activity before birth. The aims of this study were to determine the effect of suppressing allopregnanolone production on behavioral responses to transient asphyxia in late gestation fetal sheep using the 5α-reductase (R)-2 inhibitor, finasteride. Specificity of the effects of finasteride was assessed by co-infusion of alfaxalone, a synthetic analog of allopregnanolone. Fetal catheters and electrodes for measurement of the electrocorticogram (ECoG) and nuchal electromyogram were implanted at 125 days of gestation, and an inflatable occluder was placed to allow umbilical cord occlusion (UCO). At approximately 130 days of gestation, fetuses received carotid arterial infusion of vehicle (2-hydroxypropyl-β-cyclodextrin; 40% w/vol), finasteride (40 mg/kg/h), alfaxalone (5 mg/kg/h), or finasteride + alfaxalone. A further three groups of fetuses were subjected to 5 min UCO at 30 min after the start of each infusion regime. Finasteride treatment alone increased the incidence of arousal-like activity; this was reduced by co-infusion of alfaxalone. After UCO, finasteride treatment caused a prolongation of sub-low voltage (LV) ECoG activity and increase in aberrant ECoG spike activity when compared to vehicle-treated UCO fetuses. After UCO, alfaxalone treatment reduced the incidence of sub-LV, reduced the number of aberrant EEG spikes, and restored ECoG activity to the pattern observed after UCO in vehicle-treated fetuses. These results confirm that neurosteroids significantly modulate normal CNS activity in the late gestation fetus, modify, and limit the effects of asphyxia on the brain.
authors.affiliation: Monash Institute of Medical Research, The Ritchie Centre, Clayton, Vic., 3168, Australia. tamara.yawno@med.monash.edu.au
authors.forename: Tamara
authors.initials: T
authors.lastname: Yawno
authors.forename: Edwin B
authors.initials: EB
authors.lastname: Yan
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hirst
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
mesh_terms: D000818:Animals; D001143:Arousal / Q000187:drug effects; D001237:Asphyxia / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects / Q000662:veterinary; D004576:Electromyography; D005333:Fetus / Q000187:drug effects*; D018120:Finasteride / Q000494:pharmacology*; D006340:Heart Rate, Fetal / Q000187:drug effects; D011277:Pregnanediones / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000502:physiology; D034561:Sheep, Domestic; D012890:Sleep / Q000502:physiology
chemical_list: D011277:Pregnanediones; D011963:Receptors, GABA-A; D018120:Finasteride; C006477:alphaxalone