title: Oligodendroglial maldevelopment in the cerebellum after postnatal hyperoxia and its prevention by minocycline.
abstract: 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.
authors.affiliation: Department for Neonatology, Charité University Medical Center, Berlin, Germany.|Institute of Bioanalytics, Technische Universität Berlin, Berlin, 13353, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Scheuer
authors.affiliation: Department for Neonatology, Charité University Medical Center, Berlin, Germany.
authors.forename: Vivien
authors.initials: V
authors.lastname: Brockmöller
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Marissa
authors.initials: M
authors.lastname: Blanco Knowlton
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jörn-Hendrik
authors.initials: JH
authors.lastname: Weitkamp
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Torben
authors.initials: T
authors.lastname: Ruhwedel
authors.affiliation: Center for Stroke Research, Charité University Medical Center, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Mueller
authors.affiliation: Department for Neonatology, Charité University Medical Center, Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Endesfelder
authors.affiliation: Department for Neonatology, Charité University Medical Center, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bührer
authors.affiliation: Department for Neonatology, Charité University Medical Center, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitz
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D018496:Hyperoxia / Q000473:pathology* / Q000517:prevention & control*; D008911:Minocycline / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013234:Stem Cells / Q000187:drug effects
chemical_list: D016207:Cytokines; D009419:Nerve Tissue Proteins; D008911:Minocycline
keywords: cerebellum; hyperoxia; minocycline; oligodendroglia; preterm infants; white matter damage