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.