School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle, Australia.
Brain Behav. 2024 Sep;14(9):e70009. doi: 10.1002/brb3.70009.
Preterm birth is associated with brain injury and long-term behavioral abnormalities, for which there are limited prevention options. When born preterm, infants prematurely lose placental neurosteroid (allopregnanolone) support. This increases the risk of excitotoxic damage to the brain, which increases the risk of injury, causing long-term deficits in behavior, myelination, and alterations to neurotransmitter pathways. We propose that postnatal restoration of neurosteroid action through zuranolone therapy will reduce neurological impairments following preterm birth.
Guinea pig dams underwent survival cesarean section surgery to deliver pups prematurely (GA64) or at term (GA69). Between birth and term equivalence age, preterm pups received vehicle (15% β-cyclodextrin) or the allopregnanolone analogue zuranolone (1 mg/kg/day). Behavioral analysis was performed at postnatal day (PND) 7 and 40, before tissue collection at PND 42. Immunostaining for myelin basic protein (MBP), as well as real-time polymerase chain reaction to characterize oligodendrocyte lineage and neurotransmitter pathways, was performed in frontal cortex tissues.
Zuranolone treatment prevented the hyperactive phenotype in preterm-born offspring, most markedly in males. Additionally, preterm-related reductions in MBP were ameliorated. Several preterm-related alterations in mRNA expression of dopaminergic, glutamatergic, and GABAergic pathways were also restored back to that of a term control level.
This is the first study to assess zuranolone treatment as a neuroprotective therapy following preterm birth. Zuranolone treatment improved behavioral outcomes and structural changes in the preterm offspring, which continued long term until at least a late childhood timepoint. Clinical studies are warranted for further exploring the neuroprotective possibilities of this treatment following preterm birth.
早产与脑损伤和长期行为异常有关，而针对这些问题的预防措施有限。早产儿会过早失去胎盘神经甾体（别孕烯醇酮）的支持。这增加了大脑兴奋性毒性损伤的风险，从而增加了损伤的风险，导致行为、髓鞘形成和神经递质途径改变的长期缺陷。我们提出，通过 zuranolone 治疗恢复产后神经甾体作用将减少早产出生后神经损伤。
豚鼠孕鼠接受存活剖宫产手术以早产（GA64）或足月（GA69）分娩。在出生到足月等效年龄之间，早产儿接受载体（15%β-环糊精）或别孕烯醇酮类似物 zuranolone（1mg/kg/天）。在组织采集前（PND42），在出生后第 7 天和 40 天进行行为分析。对额皮质组织进行髓鞘碱性蛋白（MBP）免疫染色以及实时聚合酶链反应以表征少突胶质细胞谱系和神经递质途径。
Zuranolone 治疗可预防早产出生的后代出现多动表型，尤其是雄性。此外，还改善了与早产相关的 MBP 减少。多巴胺能、谷氨酸能和 GABA 能途径与早产相关的几种 mRNA 表达改变也恢复到足月对照水平。
这是第一项评估 zuranolone 治疗作为早产出生后神经保护治疗的研究。Zuranolone 治疗改善了早产后代的行为结果和结构变化，并持续到至少儿童后期时间点。需要进行临床研究以进一步探索这种治疗方法在早产出生后的神经保护可能性。
