背景:早产与脑损伤和长期行为异常有关,有有限的预防选择。出生时早产,婴儿过早失去胎盘神经类固醇(别孕烯醇酮)支持。这增加了大脑兴奋性毒性损伤的风险,这增加了受伤的风险,造成长期的行为缺陷,髓鞘形成,以及神经递质通路的改变。我们建议通过zuranolone治疗产后恢复神经类固醇作用将减少早产后的神经系统损害。
方法:豚鼠母猪行存活剖宫产手术,以早产(GA64)或足月分娩(GA69)。在出生和等值年龄之间,早产幼崽接受载体(15%β-环糊精)或别孕烯醇酮类似物zuranolone(1mg/kg/天).在出生后第7天和第40天进行行为分析,然后在PND42处收集组织。髓鞘碱性蛋白(MBP)的免疫染色,以及实时聚合酶链反应来表征少突胶质细胞谱系和神经递质途径,在额叶皮质组织中进行。
结果:Zuranolone治疗可预防早产后代的过度活跃表型,在男性中最明显。此外,早产相关的MBP减少得到改善.多巴胺能mRNA表达的几种早产相关改变,谷氨酸能,GABA能途径也恢复到足月对照水平。
结论:这是第一项评估Zuranolone治疗作为早产后神经保护疗法的研究。Zuranolone治疗改善了早产后代的行为结果和结构变化,这种情况一直持续到至少一个童年晚期的时间点。临床研究有必要进一步探索早产后这种治疗的神经保护可能性。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.