School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
Mothers and Babies Research Centre, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
Dev Psychobiol. 2024 Nov;66(7):e22554. doi: 10.1002/dev.22554.
The 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.
产后环境对早产儿来说是具有挑战性的，他们会暴露在缺氧和兴奋毒性事件中，而胎盘来源的神经甾体的过早丧失会加剧这种情况。在早产到足月相等的年龄（TEA）期间，尽管存在这些挑战，小脑仍在继续发育。我们假设在此期间进行神经甾体替代治疗将支持最佳的小脑发育。豚鼠母猪在足月（约 69 天妊娠）时分娩，或被诱导早产（约 62 天），早产仔猪在 TEA 前接受 ganaxolone 或载体。产后评估包括唾液皮质醇（校正产后年龄 [CPA] 0、7、38）、行为分析（CPA7、38）和组织采集（CPA0 和 CPA40）。通过免疫组织化学评估小脑中的神经发育标志物（MBP、Olig2 和 NeuN），而 RT-PCR 用于研究关键的抑制/兴奋途径和少突胶质细胞谱系标志物。早产后，出现了一种过度活跃的表型，唾液皮质醇浓度增加，髓鞘形成和少突胶质细胞成熟在蛋白质水平受损。关键抑制/兴奋途径和髓鞘稳定性的 mRNA 表达也在早产后发生改变。重要的是，我们表明神经甾体替代治疗使小脑的发育和行为恢复到类似于足月的表型。因此，ganaxolone 可能降低小脑对早产儿出生后挑战的易感性。
