Deleterious Effect of Hyperoxia at Birth on White Matter Damage in the Newborn Rat

Abstract

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.

Intratracheal transplantation of mesenchymal stem cells simultaneously attenuates both lung and brain injuries in hyperoxic newborn rats

“…Furthermore, rats at P3 and P6, but not at P10, showed hypomyelination upon exposure to 80% oxygen (15). In the study by Vottier et al (22), white matter myelin content and mature oligodendrocyte density at P10 were significantly reduced by postnatal hyperoxia for 7 d, but >2-fold increase in ED1-and TUNEL-positive cells at P3 tended to subside at P10, and significantly increased GFAP positive cells at P3 became normalized at P10. There were no significant differences in several neurotrophic factors, such as BDNF and VEGF, between the study groups.…”

Effect of oxygen inhalation on cerebral blood flow velocity in premature neonates

“…It has been observed in experimental animals that hyperoxemia increases apoptotic cell death and white matter damage (14,15). The vulnerability to oxygen-induced cell death is age dependent and the maximal incidence is observed during the first week of life (16).…”

Newborn blood gas derangements of children born extremely preterm and neurocognitive dysfunctions at age 10 years

“…(Gerstner et al, 2008; Leviton et al, 2010; Vottier et al, 2011) Although the dysfunctions at age 10 years differ from those assessed at age 2 years, we continue to see the diversity and lack of cohesiveness of associated dysfunctions.…”

“…Although some observers want to emphasize hypoxia as a cause of brain injury in preterm newborns, (Salmaso et al, 2014; Volpe, 2009) other blood gas derangements, including hyperoxemia,(Gerstner et al, 2008; Leviton et al, 2010; Vottier et al, 2011) hypocapnia (hypocarbia),(Dammann et al, 2001; Fritz and Delivoria-Papadopoulos, 2006; Leviton et al, 2010) hypercapnia,(Fritz and Delivoria-Papadopoulos, 2006; Hagen et al, 2008; Leviton et al, 2010) and acidemia (acidosis)(Lavrijsen et al, 2005; Leviton et al, 2010) either are capable of contributing to brain damage in the immature brain, or are closely linked with related phenomena. We know of no study of the relationship between indicators of oxygenation or of carbon dioxide exchange shortly after birth among extremely preterm newborns and neurocognitive functions 10 years later.…”