[Abstract Title]. - Society for Neuroscience

1 M&BRC and Sch. of Biomed Sc, Univ. Newcastle, Callaghan, Newcastle, Australia; 2 Hunter
Med. Res. Inst., Newcastle, Australia; 3 Physiol., Monash Univ., Melbourne, Australia
Abstract: Neurosteroids have potent neuroprotective actions in the fetal and adult brain. We
have previously shown that the key neurosteroidogenic enzyme, 5α reductase (5αR), is
upregulated in response to acute hypoxia in the fetus and the resultant increase in 5αR-reduced
steroids decreases hypoxia-induced apoptotic cell death in the hippocampus. Repeated treatment
with betamethasone (a synthetic corticosteroid), may suppress levels of 5αR, resulting in brain
injury.
The aim of this study was to determine the effect of repeated betamethasone treatment on the
expression of key enzymes in the neurosteroid synthethesis pathway and on the level of apoptotic
cell death in normal and growth restricted fetal brains. Placental insufficiency in guinea pigs was
produced by the ablation of uterine artery branches at mid gestation (term 68d) in order to induce
fetal growth restriction. Sham and growth restriction fetuses were treated with vehicle or
betamethasone (1mg/kg/day) for 4 days prior to sacrifice (65d). Western blot and real time PCR
were used to quantify the effects on key neurosteroidogenic enzymes (5αR and P450scc) in fetal
brains, adrenal glands and placenta. Activated caspase-3 immunolabelling in the fetal brains
were used to assessed levels of apoptotic cell death. Betamethasone treatment reduced 5αR
expression in the placenta by 51% (P=0.029), but not in the brain. Apoptosis significantly
increased in the cortex, CA1 and dentate regions of the hippocampus with betamethasone
treatment. There was no additive effect when betamethasone was combined with growth
restriction on either 5αR expression or apoptosis, however there were reductions in the
expression of glutamate transporter GLAST in glial cells and reductions in microtubule
associated protein 2 (MAP-2) in neurons in regions of the cortex and hippocampus of growth
restricted animals. The decrease in 5αR in the placenta with betamethasone treatment may
reduce fetal brain concentrations of neurosteroids. This reduction in fetal brain neurostreroids
and the concomitant reductions in GLAST expression may impair neuroprotective mechanisms,
increasing the sensitivity of the fetuses to excitotoxic brain injury.
Disclosures: R.K. Sullivan, None; H.K. Palliser, None; A.A. McKendry, None; D.W.
Walker, None; J.J. Hirst, None; D.M. Yates, None.
Poster
232. Developmental Cell Death: Biological Effects
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 232.7/B47
Topic: A.06.a. Developmental cell death: Biological effects
Support: NIH Grant HD055365