Deleterious Effect of Hyperoxia at Birth on White Matter Damage in the Newborn RatVottier G. · Pham H. · Pansiot J. · Biran V. · Gressens P. · Charriaut-Marlangue C. · Baud O.
aINSERM, AVENIR R05230HS (U676), Université Paris 7, Faculté de Médecine Denis Diderot, IFR 02, bPremUP, cNeonatal Intensive Care Unit, Hôpital Robert Debré, APHP, and dINSERM, U676, Paris, France
White matter damage (WMD) remains the leading cause of cerebral palsy in children born prematurely. The release of an excessive amount of reactive oxygen species is recognized as a risk factor for WMD. We hypothesize that free radical injury during reoxygenation at birth may be harmful to the immature white matter and may underlie, at least in part, the pathogenesis of WMD. We tested this hypothesis in rat pups delivered from normoxic pregnant rats, and by investigating an animal model based on protracted antenatal hypoxia in the pregnant rat and mimicking the main features of human WMD in rat pups. From embryonic day (E)5 to E21, the pregnant rats were placed in a chamber supplied with a gas mixture that either induced hypoxia (FiO2 = 10%) or maintained normoxia (FiO2 = 21%). On E21, the dams were removed from the chamber and housed under either normoxia (FiO2 = 21%), hyperoxia (FiO2 = 60%) or slowly reoxygenated (FiO2 from 15% at E21 to 21% at postnatal day 7). Postnatal hyperoxia was associated with a significantly increased density of activated microglial cells (+105%) and TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling)-positive cells (+85%) within the developing white matter. Myelin content (–31%) and mature oligodendrocyte density (–37%) in the normal developing white matter were significantly decreased by postnatal hyperoxia. Postnatal hyperoxia significantly potentiated the myelination delay and oligodendroglial dysmaturation induced by antenatal hypoxia. In contrast, progressive reoxygenation at birth did not induce any change in white matter inflammation, myelination and cell death as compared with normoxic controls, and prevented most of the WMD observed following antenatal hypoxia. This study demonstrates a deleterious effect of hyperoxia at birth on the developing white matter in normal rat pups. Postnatal hyperoxia worsened the WMD induced by antenatal hypoxia. Hyperoxia at birth should be avoided in preterm infants at risk of WMD.
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