Pavy Carlton L, Shaw Julia C, Palliser Hannah K, Moloney Roisin A, Hirst Jonathan J
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
Mothers and Babies Research Centre, Hunter Medical Research Institute, Newcastle, Australia.
J Dev Orig Health Dis. 2025 Jan 8;16:e2. doi: 10.1017/S2040174424000394.
Preterm birth exposes the neonate to hypoxic-ischaemic and excitotoxic insults that impair neurodevelopment and are magnified by the premature loss of placentally supplied, inhibitory neurosteroids. The cerebellum is a neuronally dense brain region, which undergoes critical periods of development during late gestation, when preterm births frequently occur. We propose that neurosteroid replacement therapy using tiagabine and zuranolone will protect the cerebellum against preterm-associated insults. Guinea pig dams received c-section surgery preterm (gestational age (GA) 64) or at term (GA70) with preterm pups administered tiagabine (2.5 mg/kg/day), zuranolone (1 mg/kg/day) or vehicle (15% β-cyclodextrin) until term equivalent age (GA70). Behavioural testing was performed at corrected postnatal day 8 (PND8) and PND41 with tissue collection occurring at PND42. Neurodevelopmental markers (MBP, OLIG2 and NeuN) were assessed within the cerebellum by immunohistochemistry, whilst GABAergic and glutamatergic pathway expression was quantified using high throughput RT-PCR. Zuranolone and, to a lesser extent, tiagabine were able to protect against hyperactive behaviour at PND8 in males, whilst in females, a less marked hyperactive phenotype was present with neither treatment impacting behaviour further. Both treatments improved MBP staining, whilst tiagabine was found to restore oligodendrocyte maturation in females only. GABAergic and glutamatergic pathway expression was found to be restored by both treatments in females. Overall, this study demonstrates the neuroprotective attributes of neurosteroid replacement therapy using tiagabine and zuranolone, thereby demonstrating their potential to mitigate long-term neurodevelopmental impairments. Furthermore, the sexually dimorphic effects observed suggest future investigations may show increased benefit by using sex-specific treatment regimes.
早产会使新生儿遭受缺氧缺血和兴奋性毒性损伤，这些损伤会损害神经发育，并且由于胎盘供应的抑制性神经甾体过早丧失而加剧。小脑是神经元密集的脑区，在妊娠后期会经历关键的发育阶段，而这一时期经常发生早产。我们提出，使用噻加宾和 zuranolone 进行神经甾体替代疗法将保护小脑免受早产相关损伤。豚鼠母鼠在早产（孕龄（GA）64）或足月（GA70）时接受剖宫产手术，早产幼崽给予噻加宾（2.5 毫克/千克/天）、zuranolone（1 毫克/千克/天）或赋形剂（15%β-环糊精），直至足月等效年龄（GA70）。在矫正出生后第 8 天（PND8）和 PND41 进行行为测试，并在 PND42 收集组织。通过免疫组织化学评估小脑中的神经发育标志物（髓鞘碱性蛋白（MBP）、少突胶质细胞转录因子 2（OLIG2）和神经元核抗原（NeuN）），同时使用高通量逆转录聚合酶链反应（RT-PCR）对 GABA 能和谷氨酸能通路表达进行定量。Zuranolone 以及在较小程度上的噻加宾能够预防雄性 PND8 时的多动行为，而在雌性中，存在不太明显的多动表型，两种治疗均未进一步影响行为。两种治疗均改善了 MBP 染色，而仅发现噻加宾能恢复雌性少突胶质细胞的成熟。两种治疗均使雌性的 GABA 能和谷氨酸能通路表达恢复。总体而言，本研究证明了使用噻加宾和 zuranolone 进行神经甾体替代疗法的神经保护特性，从而证明了它们减轻长期神经发育损伤的潜力。此外，观察到的性别差异效应表明，未来的研究可能会显示使用性别特异性治疗方案会带来更大的益处。
