8 Impact of Inhaled Nitric Oxide on Hyperoxia-Induced White Matter Damage in Neonatal Rats

White matter damage (WMD) and chronic lung disease (CLD) are the two main complications occurring in very preterm infants. Clinical and experimental evidence suggest that the use of high oxygen in preterm infants lead to both WMD and CLD. Inhaled nitric oxide (iNO) has been proposed to promote alveolarization in the developing lung, and we have reported that iNO promotes myelination and induces neuroprotection in neonatal rats with excitotoxic brain damage. We made the hypothesis that iNO may be neuroprotective in rat pups exposed to hyperoxia. Pregnant rats were randomly assigned to hyperoxia (80% O2) or normoxia for 8 days (E21 to postnatal day (P) 7). Both groups received iNO (5 ppm) or air from E21 to P7. Animals were evaluated at P3, P10 and P21 using immunohistochemistry, cognitive functions and mass spectrometry imaging. iNO significantly attenuated the severity of hyperoxia-induced WMD induced in neonatal rats. Specifically, iNO decreased white matter inflammation, cell death, and enhanced the density of developing oligodendrocytes and oligodendroglial maturation. Furthermore, iNO triggered an early upregulation of P27kip1 and brain-derived growth factor (BDNF). Whereas hyperoxia disrupted early associative abilities, iNO treatment maintained learning scores to a level similar to that of control pups. In contrast to its marked neuroprotective effects, iNO induced only small and transient improvements of CLD. These findings suggest that iNO exposure at low doses is specifically neuroprotective in an animal model combining simultaneously injuries of the developing lung and brain that mimicked CLD and WMD in preterm infants.