Potential neurosteroid replacement therapy following premature birth and fetal growth restriction

Events during gestation and changes in the intrauterine environment contribute to abnormal development and injury in the immature brain,influencing health and disease throughout life. Progesterone and its neuroactive steroid metabolite, allopregnanolone, are present in high concentrations during pregnancy. Allopregnanolone signalling at the GABAA receptor has important trophic and neuroprotective effects. The disruption of neuroactive steroid concentrations due to complications such as intrauterine growth restriction (IUGR) or preterm birth may therefore adversely affect brain development and increase perinatal brain injury. Inhibition of allopregnanolone synthesis was assessed in fetal guinea pigs after surgery to induce IUGR. Both fetal brain and plasma allopregnanolone concentrations were reduced by finasteride treatment. Finasteride treatment and IUGR were associated with reduced myelination and IUGR with increased astrocyte activation in the brain. A model of premature birth (0.87 gestation) was developed in the guinea pig to assess the effect of preterm postnatal changes in neuroactive steroid concentrations on the developing brain. Preterm guinea pigs exhibited less activity, higher mortality rates, reduced allopregnanolone concentrations and lower expression of steroid synthetic enzymes. Myelination in the hippocampus and cerebellum was also suppressed. The potential of postnatal replacement of neuroactive steroids by progesterone treatment was examined in preterm neonates. Following progesterone therapy, cortisol levels were elevated, with implications for development. Sex differences were noted in plasma neuroactive steroid concentrations. Brain allopregnanolone concentrations in preterm neonates were increased at postnatal days 1 and 8 by progesterone administration. Exploratory behaviours were altered in progesterone treated preterm animals, demonstrating changes in brain function associated with treatment. This thesis identifies changes in the perinatal guinea pig brain associated with altered neuroactive steroid concentrations and establishes the efficacy of progesterone replacement therapy in augmenting the endogenous synthesis of allopregnanolone in the preterm brain. Long-term studies to establish the developmental outcomes of postnatal progesterone/neuroactive steroid replacement after preterm birth and in combination with complications such as IUGR, hypoxic insults and infection are needed to identify new, safe and effective treatment options.