ESA-SRB-AOTA 2019

Dose optimisation to mimic the in utero neurosteroid environment in preterm neonates (#727)

Julia C Shaw 1 2 , Rebecca M Dyson 3 4 , Hannah K Palliser 1 2 , Ryan Sixtus 3 4 , Heather Barnes 3 4 , Maureen Prowse 3 4 , Clint Gray 3 4 , Max J Berry 3 4 , Jonathan J Hirst 1 2
  1. Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
  2. University of Newcastle, New Lambton Heights, NSW, Australia
  3. Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
  4. Centre for Translational Physiology, University of Otago, Wellington, New Zealand

Introduction: Approximately 10% of births in Australia are preterm and it is now established that these vulnerable neonates have myelination deficits, which are exacerbated by early exposure to the ex utero environment and reduced inhibitory tone. We propose this is due to the early loss of the placentally-derived neurosteroid, allopregnanolone. We have previously shown that postnatally restoring inhibitory neurosteroid action following preterm birth using the allopregnanolone analogue ganaxolone, can restore myelination. The aim of the current study is to determine the lowest effective dose of ganaxolone to ensure restoration of myelination, but minimisation of sedation-related side effects.

Methods: Dunkin Hartley guinea pigs had labour induced to deliver neonates prematurely at gestational age 62 (term=GA69). Between birth and term equivalence age, preterm neonates received either 45% β-cyclodextrin (vehicle), 0.5mg/kg/day (low-GNX), 1mg/kg/day (mid-GNX), or 2.5mg/kg/day ganaxolone (high-GNX) twice daily via subcutaneous injection. Physical characteristics, blood sugar levels and well-being scores (indicator of activity, respiration, and posture) were monitored throughout with tissue collection occurring at term equivalence age.

Results: There was no difference in weight gain between the neonates receiving vehicle and those receiving GNX. Ponderal index was decreased for high-GNX males on postnatal day 1 (PND1), compared to those receiving vehicle. Daily non-fasting blood sugar averages were reduced for high-GNX males and females across PND3-6 compared to their vehicle counterparts. Well-being scores were also reduced in both sexes receiving high-GNX across PND1-3 compared to the vehicle neonates, and this was more pronounced 2 hours post drug treatment.

Conclusion: Based on preliminary analysis, a high dose of ganaxolone has defined effects on sedation (indicated by well-being score) and metabolism (indicated by ponderal index and blood sugar levels), which may limit the feasibility of this particular dose, whereas lower doses were without these effects. Further analysis, particularly of myelination in the brain, is required.