Poster Presentation & Flash Talk 46th Annual Meeting of the Fetal and Neonatal Physiological Society 2019

Emapunil improves adverse neurobehavioural outcomes following exposure to stressful events in pregnancy (#150)

Gabrielle K Crombie 1 2 , Hannah K Palliser 1 2 , Julia C Shaw 1 2 , Deborah M Hodgson 3 , David W Walker 4 , Jonathan J Hirst 1 2
  1. Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
  2. School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia
  3. School of Psychology, University of Newcastle, Newcastle, NSW, Australia
  4. School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia

Background: Pregnancy compromises lead to life-long neurodevelopmental programming that markedly increase the risk of behavioural disorders in later life. Chronic stress exposure in pregnancy has been shown to disrupt neurosteroid synthesis, decreasing important neuroprotective myelination processes, resulting in an increased risk of disorders including attention deficit hyperactivity disorder (ADHD). We propose that stimulation of neurosteroid synthesis through administration of a ligand (Emapunil) of the mitochondrial translocator protein (TSPO) will reduce these adverse outcomes.

Methods:  Pregnant guinea pigs were exposed to control-handling or stress (strobe light exposure for 2hrs/day, gestational age 50, 55, 60 and 65 (term 70)). In the neonatal period, offspring were allocated to receive emapunil (0.3mg/kg daily) or vehicle (45% β-cyclodextrin) on postnatal day (PND) 2-8 and underwent open field and elevated plus maze testing on PND28. Mature myelination was assessed by myelin basic protein immunohistochemistry.

Results: At PND28, the prenatally-stressed males showed a hyperactive phenotype when compared to control in the open field arena, displaying increased line crossings (p=0.038), entries into the inner zone (p=0.046) and distance in the inner zone (p=0.035). This phenotype was also displayed in the elevated plus maze with prenatally-stressed males displaying increased distance travelled in the open arm (p=0.013) and closed arm (p=0.028) and increased time spent freezing (p=0.0004). The prenatally-stressed neonates that were treated with emapunil did not show these hyperactive patterns of behaviour (p>0.05). Myelination was decreased at PND30 in the prenatally-stressed males (p=0.008) whereas control levels of myelination was seen with emapunil treatment (p=0.97).

Conclusions: This study supports the negative role of prenatal stress in programming for neurobehavioural disorders, and that therapeutic interventions that involve TSPO-mediated upregulation of steroid synthesis pathways during the early neonatal period can reverse negative outcomes. The role of neurosteroids in programming the activity of GABAergic inhibitory pathways and promotion of myelination warrants further examination.