Scheuer Till, Brockmöller Vivien, Blanco Knowlton Marissa, Weitkamp Jörn-Hendrik, Ruhwedel Torben, Mueller Susanne, Endesfelder Stefanie, Bührer Christoph, Schmitz Thomas
Department for Neonatology, Charité University Medical Center, Berlin, Germany.
Institute of Bioanalytics, Technische Universität Berlin, Berlin, 13353, Germany.
Glia. 2015 Oct;63(10):1825-39. doi: 10.1002/glia.22847. Epub 2015 May 12.
According to recent research, brain injury after premature birth often includes impaired growth of the cerebellum. However, causes of cerebellar injury in this population are poorly understood. In this study, we analyzed whether postnatal hyperoxia perturbs white matter development of the cerebellum, and whether cerebellar glial damage can be prevented by minocycline. We used a hyperoxia model in neonatal rats providing 24 h exposure to fourfold increased oxygen concentration (80% O2) from P6 to P7, followed by recovery in room air until P9, P11, P15, P30. Injections with minocycline were performed at the beginning and 12 h into hyperoxia exposure. Hyperoxia induced oxidative stress in the cerebellum at P7 as evidenced by increased nitrotyrosine concentrations. Numbers of proliferating, NG2+Ki67+ oligodendroglial precursor cells were decreased at P7 after hyperoxia and at P11 following recovery in room air. Numbers of mature, CC1+ oligodendrocytes were diminished in recovering hyperoxia rats, and myelin basic protein expression was still decreased at P30. Electron microscopy analysis of myelinated fibers at P30 revealed thinner myelin sheath after hyperoxia. Long-term injury of the cerebellum by neonatal hyperoxia was confirmed by reduced volumes in MRI measurements at P30. In response to 80% O2, expression of platelet-derived growth factor (PDGF)-A was largely reduced in cerebellar tissue and also in cultured cerebellar astrocytes. Treatment with minocycline during hyperoxia prevented oxidative stress, attenuated oligodendroglial injury, and improved astroglial PDGF-A levels. In conclusion, early hyperoxia causes white matter damage in the cerebellum with astroglial dysfunction being involved, and both can be prevented by treatment with minocycline. Neonatal exposure to hyperoxia causes hypomyelination of the cerebellum. Reduced astroglial growth factor production but not microglial inflammation seems to contribute to oligodendroglial damage, and minocycline rescues oligodendroglia development in the cerebellum after hyperoxia.
根据最近的研究，早产后脑损伤通常包括小脑发育受损。然而，该人群中小脑损伤的原因尚不清楚。在本研究中，我们分析了出生后高氧是否会扰乱小脑白质发育，以及米诺环素是否可以预防小脑神经胶质损伤。我们使用新生大鼠高氧模型，从出生后第6天（P6）至第7天（P7）让其暴露于四倍增加的氧浓度（80% O₂）下24小时，随后在室内空气中恢复至P9、P11、P15、P30。在高氧暴露开始时和暴露12小时后注射米诺环素。高氧在P7时诱导小脑氧化应激，这可通过硝基酪氨酸浓度增加得以证明。高氧后P7时增殖的、NG2⁺Ki67⁺少突胶质前体细胞数量减少，在室内空气中恢复后P11时数量仍减少。恢复中的高氧大鼠成熟的CC1⁺少突胶质细胞数量减少，且在P30时髓鞘碱性蛋白表达仍降低。P30时对有髓纤维的电子显微镜分析显示高氧后髓鞘变薄。P30时MRI测量体积减小证实了新生期高氧对小脑的长期损伤。响应80% O₂时，血小板衍生生长因子（PDGF）-A在小脑组织以及培养的小脑星形胶质细胞中的表达大幅降低。高氧期间用米诺环素治疗可预防氧化应激，减轻少突胶质损伤，并改善星形胶质细胞的PDGF-A水平。总之，早期高氧会导致小脑白质损伤并伴有星形胶质细胞功能障碍，两者均可通过米诺环素治疗预防。新生期暴露于高氧会导致小脑髓鞘形成不足。星形胶质细胞生长因子产生减少而非小胶质细胞炎症似乎导致少突胶质细胞损伤，米诺环素可挽救高氧后小脑少突胶质细胞的发育。
