Changes in Neuroactive Steroid Concentrations After Preterm Delivery in the Guinea Pig

Abstract

Background: Preterm birth is a major cause of neurodevelopmental disorders. Allopregnanolone, a key metabolite of progesterone, has neuroprotective and developmental effects in the brain. The objectives of this study were to measure the neuroactive steroid concentrations following preterm delivery in a neonatal guinea pig model and assess the potential for postnatal progesterone replacement therapy to affect neuroactive steroid brain and plasma concentrations in preterm neonates. Methods: Preterm (62-63 days) and term (69 days) guinea pig pups were delivered by cesarean section and tissue was collected at 24 hours. Plasma progesterone, cortisol, allopregnanolone, and brain allopregnanolone concentrations were measured by immunoassay. Brain 5a-reductase (5aR) expression was determined by Western blot. Neurodevelopmental maturity of preterm neonates was assessed by immunohistochemistry staining for myelination, glial cells, and neurons. Results: Brain allopregnanolone concentrations were significantly reduced after birth in both preterm and term neonates. Postnatal progesterone treatment in preterm neonates increased brain and plasma allopregnanolone concentrations. Preterm neonates had reduced myelination, low birth weight, and high mortality compared to term neonates. Brain 5aR expression was also significantly reduced in neonates compared to fetal expression. Conclusions: Delivery results in a loss of neuroactive steroid concentrations resulting in a premature reduction in brain allopregnanolone in preterm neonates. Postnatal progesterone therapy reestablished neuroactive steroid levels in preterm brains, a finding that has implications for postnatal growth following preterm birth that occurs at a time of neurodevelopmental immaturity.

Long-term effects of preterm birth on behavior and neurosteroid sensitivity in the guinea pig

“…Additionally, the results indicate that there are sex differences in the influences of prematurity on these parameters, with males seemingly more affected by early delivery. Furthermore, one of the most important findings was that the deficiencies in neurodevelopment of ex-preterm males seen previously in neonates remained until juvenility, whereas females were able to restore their initial reductions (25,26). Our previous studies in guinea pigs showed markers of mature oligodendrocytes were reduced in preterm compared to term gestational age fetuses, and were markedly affected by preterm delivery in the neonatal hippocampus and subcortical white matter in both sexes (25,26).…”

“…Furthermore, one of the most important findings was that the deficiencies in neurodevelopment of ex-preterm males seen previously in neonates remained until juvenility, whereas females were able to restore their initial reductions (25,26). Our previous studies in guinea pigs showed markers of mature oligodendrocytes were reduced in preterm compared to term gestational age fetuses, and were markedly affected by preterm delivery in the neonatal hippocampus and subcortical white matter in both sexes (25,26). The use of an ex-preterm juvenile model in the present study allowed us to ascertain whether oligodendrocyte expression remains affected until childhood, when many of the school-related disabilities become apparent clinically.…”

“…This reduced allopregnanolone-mediated neuroprotection increases the vulnerability of the neonatal brain to insults such as hypoxia. Furthermore, these preterm animals also show decreased myelination in the CA1 region of the hippocampus and the adjacent subcortical white matter 24 h after delivery, and in the cerebellum at term equivalence (25)(26)(27).…”

“…Our previous studies have demonstrated a dramatic drop in brain allopregnanolone concentrations following birth at term and preterm compared to fetal levels (26). This reduced allopregnanolone-mediated neuroprotection increases the vulnerability of the neonatal brain to insults such as hypoxia.…”

“…This reduced allopregnanolone-mediated neuroprotection increases the vulnerability of the neonatal brain to insults such as hypoxia. Furthermore, these preterm animals also show decreased myelination in the CA1 region of the hippocampus and the adjacent subcortical white matter 24 h after delivery, and in the cerebellum at term equivalence (25)(26)(27).In this study, we examined the effect of preterm birth on brain development, focusing on the mature myelinating oligodendrocytes and reactive astrocytes that are essential for proper neuronal circuitry and synaptic transmission, to identify effects at adolescence in guinea pigs. We also aimed to ascertain the impact that preterm delivery has on the expression of neurosteroid-sensitive GABA A receptor subunits, in addition to behavior at juvenility, with a particular focus on the hyperactive and anxious behaviors that are common to ex-preterm males and females respectively.…”