Astroglia-derived growth factors: A role in persistent oligodendroglial injury in the cerebellum after neonatal hyperoxia.

• Applicant: Privatdozent Dr. Thomas Schmitz
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240458683

Preterm birth is one of the major pediatric public health problems of our time with 1-2% of all live births being born before 32 weeks of gestation. Although the survival rate of these infants has greatly improved, many of very preterm infants acquire major neurological disabilities. The main pathology underlying is white matter damage (WMD) including hypomyelination, which so far has commonly been described in the cerebrum. However, recent studies indicate that many preterm infants suffer from WMD in the cerebellum, too. Even though the importance of the cerebellum for the development not only of motor coordination but also of complex brain functions such as cognition, memory and emotion, has increasingly been acknowledged, mechanisms of cerebellar injury are largely underinvestigated. Factors associated with WMD in the immature brain include perinatal infection, hypocapnia, and hyperoxia. The unphysiological 3- to 4-fold increase of oxygen tension caused by preterm birth into room air amounts to relative hyperoxia as compared to their natural in utero environment. This increase is mimicked in a rodent hyperoxia model exposing 6 days old rat pups to 4-fold increased oxygen concentration (80% instead of 21%). 24h to 48h exposure to hyperoxia induces increased apoptosis, decreased proliferation, and delayed maturation of oligodendroglia in the cerebrum, consequently leading to hypomyelination. So far, effects of hyperoxia on the cerebellum have not been investigated. For research on neuroprotection, anti-inflammatory and anti-oxidant properties of minocycline have intensively been investigated in various models of brain injury. The mechanisms by which minocycline exerts its protective actions have largely been attributed to inhibition of microglia. We have recently been able to identify direct protective effects of minocycline on purified oligodendroglia using an in vitro hypoxia-ischemia model. However, whether minocycline protects oligodendroglia against hyperoxia is unknown.The proposed study is designed to investigate acute and chronic injury caused by neonatal hyperoxia in the white matter of the cerebellum and to evaluate potentially protective mechanisms of minocycline. Hyperoxia-induced changes in oligodendroglia and microglia will be analyzed in rats using immunohistechemistry, realtime PCR, and Western blot. Direct cellular effects of hyperoxia will be determined in cultures of both cerebellar oligodendroglia and microglia. Protective effects of minocycline against hyperoxia will be analyzed in the white matter of the cerebellum in vivo and in cerebellar OPC cultures in vitro. Finally, long term impact of neonatal hyperoxia on myelination, ultrastructure, and total volume of the cerebellum will be analyzed in adult rats by immunohistochemistry, electron microscopy, and MRI T2 images, respectively. This complex experimental setting will provide new insights into mechanisms of both injury and protection of the immature cerebellum.

• DFG Programme: Research Grants