Impact of inhaled nitric oxide on white matter damage in growth-restricted neonatal rats

Background: Fetal growth restriction is the second leading cause of perinatal morbidity and mortality, and neonates with intrauterine growth retardation (IUGR) have increased neurocognitive and neuropsychiatric morbidity. These neurocognitive impairments are mainly related to injury of the developing brain associated with IUGR. Growing evidence from preclinical models of brain injury in both adult and neonatal rodents supports the view that nitric oxide can promote neuroprotection. Methods: In a model of IUGR induced by protracted gestational hypoxia leading to diffuse white matter injury, we subjected neonatal rats to low dose (5 ppm) but long-lasting (7 d) exposure to inhaled NO (iNO). We used a combination of techniques, including immunohistochemistry, quantitative PCR, and cognitive assessment, to assess neuroprotection. Results: Antenatal hypoxia-induced IUGR was associated with severe neuroinflammation and delayed myelination. iNO exposure during the first postnatal week significantly attenuated cell death and microglial activation, enhanced oligodendroglial proliferation and finally improved myelination. Remarkably, iNO was associated with the specific upregulation of P27kip1, which initiates oligodendrocytic differentiation. Finally, iNO counteracted the deleterious effects of hypoxia on learning abilities. Conclusion: This study provides new evidence that iNO could be effective in preventing brain damage and/or enhancing repair of the developing brain.