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 24h exposure to 4-fold 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 12h 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 MBP 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 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.

Early Life Supraphysiological Levels of Oxygen Exposure Permanently Impairs Hippocampal Mitochondrial Function

“…Furthermore, since proteomic and bioenergetic studies were done from the whole hippocampus, it is not possible to determine whether these oxygen-induced proteomic and mitochondrial functional changes were predominantly derived from neurons or glial cells or a combination of both. In this study, we focused on proteomics and mitochondrial bioenergetics only from the hippocampal homogenates, and not from regions such as cerebellum, amygdala, corpus callosum, and white matter tracts which may also are impacted by hyperoxia exposure [21][22][23] . Even though hippocampal complexes I and IV activities were measured, complex III and complex V activities were not measured due to technical difficulties and the size of the hippocampus.…”

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants

“…It is important to realize, that oxygen therapy in premature human neonates is used only to reach and maintain normoxemia. Therefore, reported models of chronic hyperoxia-induced WMI in neonatal rodents (44,45) are not considered for discussion. Experimental studies also showed that postnatal exposure to chronic hypoxia (10% O 2 for 8–10 d) reproducibly replicated human phenotype of diffuse WMI (46–48).…”

Transient Improvement of Cerebellar Oligodendroglial Development in a Neonatal Hyperoxia Model by PDGFA Treatment

“…Using a hyperoxia model for oxidative stress‐induced brain injury (Gerstner et al , ; Schmitz et al , ), we recently demonstrated long‐term injury of the cerebellar white matter caused by temporary postnatal exposure to hyperoxia (Scheuer et al , ). In this study, we investigated the impact of hyperoxia on astroglial growth factor production as an important pathway of astroglial‐oligodendroglial interplay during development.…”