Inhaled NO prevents hyperoxia-induced white matter damage in neonatal rats

Exp Neurol. 2014 Feb:252:114-23. doi: 10.1016/j.expneurol.2013.11.025. Epub 2013 Dec 7.


White matter damage (WMD) and bronchopulmonary dysplasia (BPD) are the two main complications occurring in very preterm infants. 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. Our hypothesis is that, in addition to its pulmonary effects, iNO may be neuroprotective in rat pups exposed to hyperoxia. To test this hypothesis, we exposed rat pups to hyperoxia, and we assessed the impact of iNO on WMD and BPD. Rat pups were exposed to either hyperoxia (80% FiO2) or to normoxia for 8 days. Both groups received iNO (5 ppm) or air. We assessed the neurological and pulmonary effects of iNO in hyperoxia-injured rat pups using histological, molecular and behavioral approaches. 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 proliferating 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 BPD. These findings suggest that iNO exposure at low doses is specifically neuroprotective in an animal model combining injuries of the developing lung and brain that mimicked BPD and WMD in preterm infants.

Keywords: BPD; CC3; Developing brain; Hyperoxia; MLI; Neuroprotection; Nitric oxide; RAC; WMD; White matter damage; bronchopulmonary dysplasia; cleaved caspase 3; iNO; inhaled NO; mean linear intercept; radial alveolar count; white matter damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Age Factors
  • Animals
  • Animals, Newborn
  • Blood Gas Analysis
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Death
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Disease Models, Animal
  • Female
  • Hypoxia / complications*
  • Leukoencephalopathies / etiology*
  • Leukoencephalopathies / prevention & control*
  • Lung / drug effects
  • Lung / physiopathology
  • Male
  • Neuroprotective Agents / administration & dosage*
  • Nitric Oxide / administration & dosage*
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley


  • Brain-Derived Neurotrophic Factor
  • Neuroprotective Agents
  • brain-derived growth factor
  • Cyclin-Dependent Kinase Inhibitor p27
  • Nitric Oxide