Postnatal erythropoietin treatment mitigates neural cell loss after systemic prenatal hypoxic-ischemic injury.
Postnatal erythropoietin treatment mitigates neural cell loss after systemic prenatal hypoxic-ischemic injury.
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DOI：
10.3171/2010.5.peds1032
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Robinson S
中科院分区：
文献类型：
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作者：
Mazur M;Miller RH;Robinson S
早产造成的脑损伤使儿童易患脑瘫、癫痫、认知迟缓和行为异常。中枢神经系统损伤往往在早产儿之前就开始了，这阻碍了诊断和同时治疗。迫切需要安全、有效的产后干预措施，以最大限度地减少这些慢性神经缺陷。促红细胞生成素(EPO)是一种多效性神经保护性细胞因子，但其在受损发育脑中的作用的生物学基础尚不清楚。EPO配体和受体的协同表达发生在中枢神经系统发育过程中，以促进神经细胞的存活。作者认为，孕晚期全局缺氧缺血扰乱了神经细胞EPO信号的发育调控表达，使神经细胞容易死亡。此外，作者认为新生儿外源性重组人促红细胞生成素(RhEPO)可以恢复EPO配体和受体水平的错配，提高神经细胞的存活率。胚胎第18天大鼠的短暂性全身性缺氧缺血(TSHI)模拟人类妊娠早期-晚期胎盘功能不全。这个模型被用来检验作者的假设，该模型使用了一种新的临床相关范式，即胚胎第18天的产前损伤，出生后第1天损伤后4天开始的新生儿全身注射重组人促红细胞生成素，以及对新生大鼠、幼年大鼠和成年大鼠的组织学、生化和功能分析。结果表明，胎儿期TSHI可上调脑内EPO受体，但不上调EPO配体。在少突胶质系细胞和神经元上，EPO受体持续上调，这类神经细胞特别容易因早产导致的中枢神经系统损伤而丢失。出生后给予重组人促红细胞生成素可减少组织学损伤，挽救少突胶质细胞和γ-氨基丁酸能中间神经元。与假手术对照组相比，成年大鼠损伤后髓鞘碱性蛋白表达减少，但新生大鼠经重组人促红细胞生成素治疗后，髓鞘碱性蛋白表达可恢复到接近正常水平。成年后，接受促红细胞生成素治疗的TSHI大鼠在运动技能测试中的表现明显好于接受生理盐水治疗的同龄人，并在戊四氮递增剂量范式下显示出显著的癫痫阈值恢复。这些数据表明，新生大鼠在出生前4天开始接受新的临床相关的重组人促红细胞生成素治疗，可以挽救神经细胞，并诱导成年大鼠持续的组织学和功能改善。
Brain injury from preterm birth predisposes children to cerebral palsy, epilepsy, cognitive delay, and behavioral abnormalities. The CNS injury often begins before the early birth, which hinders diagnosis and concurrent treatment. Safe, effective postnatal interventions are urgently needed to minimize these chronic neurological deficits. Erythropoietin (EPO) is a pleiotropic neuroprotective cytokine, but the biological basis of its efficacy in the damaged developing brain remains unclear. Coordinated expression of EPO ligand and receptor expression occurs during CNS development to promote neural cell survival. The authors propose that prenatal third trimester global hypoxia-ischemia disrupts the developmentally regulated expression of neural cell EPO signaling, and predisposes neural cells to death. Furthermore, the authors suggest that neonatal exogenous recombinant human EPO (rhEPO) administration can restore the mismatch of EPO ligand and receptor levels, and enhance neural cell survival. Transient systemic hypoxia-ischemia (TSHI) on embryonic Day 18 in rats mimics human early-third-trimester placental insufficiency. This model was used to test the authors’ hypothesis using a novel clinically relevant paradigm of prenatal injury on embryonic Day 18, neonatal systemic rhEPO administration initiated 4 days after injury on postnatal Day 1, and histological, biochemical, and functional analyses in neonatal, juvenile, and adult rats. The results showed that prenatal TSHI upregulates brain EPO receptors, but not EPO ligand. Sustained EPO receptor upregulation was pronounced on oligodendroglial lineage cells and neurons, neural cell populations particularly prone to loss from CNS injury due to preterm birth. Postnatal rhEPO administration after prenatal TSHI minimized histological damage and rescued oligodendrocytes and γ-aminobutyric acidergic interneurons. Myelin basic protein expression in adult rats after insult was reduced compared with sham controls, but could be restored to near normal levels by neonatal rhEPO treatment. Erythropoietin-treated TSHI rats performed significantly better than their saline-treated peers as adults in motor skills tests, and showed significant seizure threshold restoration using a pentylenetetrazole increasing-dose paradigm. These data demonstrate that neonatal rhEPO administration in a novel clinically relevant paradigm initiated 4 days after a global prenatal hypoxic-ischemic insult in rats rescues neural cells, and induces lasting histological and functional improvement in adult rats.