title: Effect of maternal administration of allopregnanolone before birth asphyxia on neonatal hippocampal function in the spiny mouse.
abstract: Clinically, treatment options where fetal distress is anticipated or identified are limited. Allopregnanolone is an endogenous steroid, that positively modulates the GABA(A) receptor, and that has anti-apoptotic and anti-excitotoxic actions, reducing brain damage in adult animal models of brain injury. We sought to determine if prophylactic treatment of the pregnant female with a single dose of this steroid could reduce birth asphyxia-induced losses in hippocampal function at 5 days of age (P5) in spiny mouse neonates (Acomys cahirinus). At 37 days gestation (term=39 days) and 1h before inducing birth asphyxia, spiny mice dams were injected subcutaneously (0.2 ml) with either 3mg/kg allopregnanolone or 20% w/v β-cyclodextrin vehicle. One hour later, fetuses were either delivered immediately by caesarean section (control group) or exposed to 7.5 min of in utero asphyxia, causing acidosis and hypoxia. At P5, ex vivo hippocampal plasticity was assessed, or brains collected to determine cell proliferation (proliferating cell nuclear antigen; PCNA) or calcium channel expression (inositol trisphosphate receptor type 1; IP(3)R1) using immunohistochemistry. Allopregnanolone partially prevented the decrease in long term potentiation at P5, and the asphyxia-induced increase in IP(3)R1 expression in CA1 pyramidal neurons. There was no effect of allopregnanolone on the asphyxia induced impairment of the input/output (I/O) curve and paired-pulse facilitation (PPF). In control birth pups, maternal allopregnanolone treatment caused significant changes in short term post-synaptic plasticity and also reduced hippocampal proliferation at P5. These findings show that allopregnanolone can modulate hippocampal development and synaptic function in a normoxic or hypoxic environment, possibly by modifying calcium metabolism. Best practice for treatment dose and timing of treatment will need to be carefully considered.
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria 3800, Australia. b.fleiss@imperial.ac.uk
authors.forename: Bobbi
authors.initials: B
authors.lastname: Fleiss
authors.forename: Helena C
authors.initials: HC
authors.lastname: Parkington
authors.forename: Harold A
authors.initials: HA
authors.lastname: Coleman
authors.forename: Hayley
authors.initials: H
authors.lastname: Dickinson
authors.forename: Tamara
authors.initials: T
authors.lastname: Yawno
authors.forename: Margie
authors.initials: M
authors.lastname: Castillo-Melendez
authors.forename: Jon J
authors.initials: JJ
authors.lastname: Hirst
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001237:Asphyxia / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D011247:Pregnancy; D011280:Pregnanolone / Q000008:administration & dosage*; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D011897:Random Allocation
chemical_list: D011280:Pregnanolone