Ganaxolone Therapy After Preterm Birth Restores Cerebellar Oligodendrocyte Maturation and Myelination in Guinea Pigs
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Wiley
2024
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| _version_ | 1867007323944255488 |
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| author | Carlton L. Pavy Julia C. Shaw Rebecca M. Dyson Hannah K. Palliser Roisin A. Moloney Ryan P. Sixtus Mary J. Berry Jonathan J. Hirst |
| author_facet | Carlton L. Pavy Julia C. Shaw Rebecca M. Dyson Hannah K. Palliser Roisin A. Moloney Ryan P. Sixtus Mary J. Berry Jonathan J. Hirst Carlton L. Pavy Julia C. Shaw Rebecca M. Dyson Hannah K. Palliser Roisin A. Moloney Ryan P. Sixtus Mary J. Berry Jonathan J. Hirst |
| collection | Wiley Open Access |
| contents | Ganaxolone Therapy After Preterm Birth Restores Cerebellar Oligodendrocyte Maturation and Myelination in Guinea Pigs Carlton L. Pavy Julia C. Shaw Rebecca M. Dyson Hannah K. Palliser Roisin A. Moloney Ryan P. Sixtus Mary J. Berry Jonathan J. Hirst Developmental Psychobiology ABSTRACTThe postnatal environment is challenging for the preterm neonate with exposure to hypoxic and excitotoxic events, amplified by premature loss of placentally derived neurosteroids. Between preterm birth and term equivalent age (TEA), cerebellar development continues despite these challenges. We hypothesize that neurosteroid replacement therapy during this time will support optimal cerebellar development. Guinea pig sows delivered at term (∼69 days gestation) or were induced to deliver preterm (∼62 days), with preterm pups receiving ganaxolone or vehicle until TEA. Postnatal assessments comprised salivary cortisol (corrected postnatal age [CPA] 0, 7, 38), behavioral analysis (CPA7, 38), and tissue collection (CPA0 and CPA40). Neurodevelopmental markers (MBP, Olig2, and NeuN) were assessed in the cerebellum by immunohistochemistry, whereas RT‐PCR was utilized to investigate key inhibitory/excitatory pathways and oligodendrocyte lineage markers. Following preterm birth, there was evidence of a hyperactive phenotype, increased salivary cortisol concentrations, and impaired myelination and oligodendrocyte maturation at the protein level. mRNA expressions of key inhibitory/excitatory pathways and myelin stability were also altered following preterm birth. Importantly, we showed that neurosteroid replacement therapy returns cerebellar development and behavior toward a term‐like phenotype. Therefore, ganaxolone may reduce the vulnerability of the cerebellum to postnatal challenges arising from preterm birth. 10.1002/dev.22554 http://creativecommons.org/licenses/by/4.0/ |
| doi_str_mv | 10.1002/dev.22554 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_dev_22554 |
| institution | Wiley Open Access |
| license_str_mv | http://creativecommons.org/licenses/by/4.0/ |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Ganaxolone Therapy After Preterm Birth Restores Cerebellar Oligodendrocyte Maturation and Myelination in Guinea Pigs Carlton L. Pavy Julia C. Shaw Rebecca M. Dyson Hannah K. Palliser Roisin A. Moloney Ryan P. Sixtus Mary J. Berry Jonathan J. Hirst Developmental Psychobiology Ganaxolone Therapy After Preterm Birth Restores Cerebellar Oligodendrocyte Maturation and Myelination in Guinea Pigs Carlton L. Pavy Julia C. Shaw Rebecca M. Dyson Hannah K. Palliser Roisin A. Moloney Ryan P. Sixtus Mary J. Berry Jonathan J. Hirst Developmental Psychobiology ABSTRACTThe postnatal environment is challenging for the preterm neonate with exposure to hypoxic and excitotoxic events, amplified by premature loss of placentally derived neurosteroids. Between preterm birth and term equivalent age (TEA), cerebellar development continues despite these challenges. We hypothesize that neurosteroid replacement therapy during this time will support optimal cerebellar development. Guinea pig sows delivered at term (∼69 days gestation) or were induced to deliver preterm (∼62 days), with preterm pups receiving ganaxolone or vehicle until TEA. Postnatal assessments comprised salivary cortisol (corrected postnatal age [CPA] 0, 7, 38), behavioral analysis (CPA7, 38), and tissue collection (CPA0 and CPA40). Neurodevelopmental markers (MBP, Olig2, and NeuN) were assessed in the cerebellum by immunohistochemistry, whereas RT‐PCR was utilized to investigate key inhibitory/excitatory pathways and oligodendrocyte lineage markers. Following preterm birth, there was evidence of a hyperactive phenotype, increased salivary cortisol concentrations, and impaired myelination and oligodendrocyte maturation at the protein level. mRNA expressions of key inhibitory/excitatory pathways and myelin stability were also altered following preterm birth. Importantly, we showed that neurosteroid replacement therapy returns cerebellar development and behavior toward a term‐like phenotype. Therefore, ganaxolone may reduce the vulnerability of the cerebellum to postnatal challenges arising from preterm birth. 10.1002/dev.22554 http://creativecommons.org/licenses/by/4.0/ |
| title | Ganaxolone Therapy After Preterm Birth Restores Cerebellar Oligodendrocyte Maturation and Myelination in Guinea Pigs |
| topic | Developmental Psychobiology |
| url | https://onlinelibrary.wiley.com/doi/10.1002/dev.22554 |