Examining Neurosteroid-Analogue Therapy in the Preterm Neonate For Promoting Hippocampal Neurodevelopment
Julia C Shaw1,2, Rebecca M Dyson3,4, Hannah K Palliser1,2
1School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.
Insights
Ganaxolone, a neurosteroid-analogue, did not improve preterm brain development markers at term equivalence. High-dose ganaxolone impaired physical wellbeing, suggesting lower doses warrant further study for potential long-term benefits.
Area of Science:
- Neuroscience
- Neonatal Development
- Pharmacology
Background:
- Preterm birth poses risks of neonatal brain injury with no current targeted therapies.
- Previous studies indicated ganaxolone promotes white matter development in preterm male guinea pigs.
- This study evaluated ganaxolone dosing for physical wellbeing and neurodevelopmental markers in preterm neonates.
Purpose of the Study:
- To assess the impact of varying ganaxolone doses on physical wellbeing and neurodevelopment in preterm guinea pigs.
- To identify safe and effective dosing strategies for ganaxolone in neonatal brain development.
- To investigate ganaxolone's effects on hippocampal neurodevelopmental markers at term equivalence.
Main Methods:
- Preterm guinea pigs (d62) and term-born controls (d69) were used.
- Preterm neonates received daily ganaxolone (0.5, 1.0, or 2.5 mg/kg) or vehicle until term equivalence.
- Physical parameters and hippocampal neurodevelopmental markers (immunohistochemistry, RT-PCR) were analyzed.
Main Results:
- High-dose ganaxolone (2.5 mg/kg) significantly impaired physical parameters including weight gain and wellbeing.
- Low and mid doses of ganaxolone showed minor impacts on early physical development.
- Preterm hippocampus exhibited deficits in oligodendrocyte, neuronal growth, and neurotransmitter system markers, unaffected by ganaxolone doses.
Conclusions:
- The highest dose of ganaxolone tested (2.5 mg/kg) negatively impacted physical health and wellbeing in preterm neonates.
- Ganaxolone did not appear to affect neurodevelopmental markers at term equivalence at the doses used.
- Further long-term studies with lower ganaxolone doses are recommended to evaluate functional outcomes for preterm-associated disorders.
Abstract:
Background: Preterm birth can lead to brain injury and currently there are no targeted therapies to promote postnatal brain development and protect these vulnerable neonates. We have previously shown that the neurosteroid-analogue ganaxolone promotes white matter development and improves behavioural outcomes in male juvenile guinea pigs born preterm. Adverse side effects in this previous study necessitated this current follow-up dosing study, where a focus was placed upon physical wellbeing during the treatment administration and markers of neurodevelopment at the completion of the treatment period. Methods: Time-mated guinea pigs delivered preterm (d62) by induction of labour or spontaneously at term (d69). Preterm pups were randomized to receive no treatment (Prem-CON) or ganaxolone at one of three doses [0.5 mg/kg ganaxolone (low dose; LOW-GNX), 1.0 mg/kg ganaxolone (mid dose; MID-GNX), or 2.5 mg/kg ganaxolone (high dose; HIGH-GNX) in vehicle (45% β-cyclodextrin)] daily until term equivalence age. Physical parameters including weight gain, ponderal index, supplemental feeding, and wellbeing (a score based on respiration, activity, and posture) were recorded throughout the preterm period. At term equivalence, brain tissue was collected, and analysis of hippocampal neurodevelopment was undertaken by immunohistochemistry and RT-PCR. Results: Low and mid dose ganaxolone had some impacts on early weight gain, supplemental feeding, and wellbeing, whereas high dose ganaxolone significantly affected all physical parameters for multiple days during the postnatal period when compared to the preterm control neonates. Deficits in the preterm hippocampus were identified using neurodevelopmental markers including mRNA expression of oligodendrocyte lineage cells (CSPG4, MBP), neuronal growth (INA, VEGFA), and the GABAergic/glutamatergic system (SLC32A1, SLC1A2, GRIN1, GRIN2C, DLG4). These deficits were not affected by ganaxolone at the doses used at the equivalent of normal term. Conclusion: This is the first study to investigate the effects of a range of doses of ganaxolone to improve preterm brain development. We found that of the three doses, only the highest dose of ganaxolone (2.5 mg/kg) impaired key indicators of physical health and wellbeing over extended periods of time. Whilst it may be too early to see improvements in markers of neurodevelopment, further long-term study utilising the lower doses are warranted to assess functional outcomes at ages when preterm birth associated behavioural disorders are observed.
