Introduction: Preterm infants born before 28 weeks of gestation are at high risk of neurodevelopmental impairment in later life. Cerebral white and gray matter injury is associated with adverse outcomes. High oxygen levels, often unavoidable in neonatal intensive care, have been identified as one of the main contributing factors to preterm brain injury. Thus, preventive and therapeutic strategies against hyperoxia-induced brain injury are needed. Erythropoietin (Epo) is a promising and also neuroprotective candidate due to its clinical use in infants as erythropoiesis-stimulating agent. Objective: The objective of this study was to investigate the effects of repetitive Epo treatment on the cerebral white matter and long-term motor-cognitive outcome in a neonatal rodent model of hyperoxia-induced brain injury. Methods: Three-day old Wistar rats were exposed to hyperoxia (48 h, 80% oxygen). Four doses of Epo (5,000 IU/kg body weight per day) were applied intraperitoneally from P3-P6 with the first dose at the onset of hyperoxia. Oligodendrocyte maturation and myelination were evaluated via immunohistochemistry and Western blot on P11. Motor-cognitive deficits were assessed in a battery of complex behavior tests (Open Field, Novel Object Recognition, Barnes maze) in adolescent and fully adult animals. Following behavior tests animals underwent post-mortem diffusion tensor imaging to investigate long-lasting microstructural alterations of the white matter. Results: Repetitive treatment with Epo significantly improved myelination deficits following neonatal hyperoxia at P11. Behavioral testing revealed attenuated hyperoxia-induced cognitive deficits in Epo-treated adolescent and adult rats. Conclusion: A multiple Epo dosage regimen protects the developing brain against hyperoxia-induced brain injury by improving myelination and long-term cognitive outcome. Though current clinical studies on short-term outcome of Epo-treated prematurely born children contradict our findings, long-term effects up to adulthood are still lacking. Our data support the essential need for long-term follow-up of preterm infants in current clinical trials.

中文翻译：

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重复促红细胞生成素治疗可减轻发育中大脑中高氧诱导的髓鞘形成不足，从而改善长期神经认知结果。

简介：妊娠 28 周之前出生的早产儿在以后的生活中出现神经发育障碍的风险很高。大脑白质和灰质损伤与不良后果相关。高氧水平在新生儿重症监护中通常是不可避免的，已被确定为早产脑损伤的主要因素之一。因此，需要针对高氧引起的脑损伤的预防和治疗策略。促红细胞生成素 (Epo) 是一种有前途且具有神经保护作用的候选药物，因为它在婴儿中作为红细胞生成刺激剂临床使用。目的：本研究的目的是探讨重复 Epo 治疗对高氧诱导脑损伤的新生啮齿动物模型脑白质和长期运动认知结果的影响。方法：三天大的 Wistar 大鼠暴露于高氧环境（48 小时，80% 氧气）。从 P3-P6 开始腹膜内施用四剂 Epo（每天 5,000 IU/kg 体重），第一剂在高氧开始时施用。通过 P11 上的免疫组织化学和蛋白质印迹评估少突胶质细胞的成熟和髓鞘形成。通过一系列复杂的行为测试（旷场、新物体识别、巴恩斯迷宫）对青少年和成年动物的运动认知缺陷进行评估。在行为测试之后，动物接受了死后扩散张量成像，以研究白质的持久微观结构变化。结果：Epo 重复治疗可显着改善 P11 新生儿高氧血症后的髓鞘形成缺陷。行为测试显示，经 Epo 治疗的青少年和成年大鼠，高氧诱导的认知缺陷有所减轻。结论：多 Epo 剂量方案可通过改善髓鞘形成和长期认知结果，保护发育中的大脑免受高氧诱导的脑损伤。尽管目前对 Epo 治疗的早产儿短期结果的临床研究与我们的研究结果相矛盾，但仍缺乏直至成年的长期效果。我们的数据支持当前临床试验中对早产儿进行长期随访的必要性。