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Updated: May 5, 2026
A Piglet Model of Neonatal Hypoxic-Ischemic Encephalopathy
Published on: May 16, 2015
Inhaled NO prevents hyperoxia-induced white matter damage in neonatal rats
Hoa Pham1, Gaelle Vottier1, Julien Pansiot1
1INSERM, UMR 676, 75019 Paris, France; Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; PremUP foundation, 75014 Paris, France.
Insights
Inhaled nitric oxide (iNO) protected neonatal rats from white matter damage (WMD) caused by hyperoxia. While iNO improved brain injury, it had minimal effects on lung complications like bronchopulmonary dysplasia (BPD).
Area of Science:
- Neonatal neurology
- Pulmonary medicine
- Developmental biology
Background:
- White matter damage (WMD) and bronchopulmonary dysplasia (BPD) are critical complications in very preterm infants.
- Inhaled nitric oxide (iNO) shows potential for promoting lung alveolarization and has demonstrated neuroprotective effects in neonatal brain injury models.
Purpose of the Study:
- To investigate the neuroprotective effects of iNO in rat pups exposed to hyperoxia, mimicking conditions relevant to preterm infants.
- To assess the impact of iNO on both white matter damage (WMD) and bronchopulmonary dysplasia (BPD) in a hyperoxia-induced injury model.
Main Methods:
- Rat pups were exposed to hyperoxia (80% FiO2) or normoxia for 8 days, with concurrent treatment of iNO (5 ppm) or air.
- Neurological and pulmonary outcomes were evaluated using histological, molecular, and behavioral assessments.
- Specific markers for inflammation, cell death, oligodendrocyte proliferation/maturation, P27kip1, and BDNF were analyzed.
Main Results:
- iNO significantly reduced hyperoxia-induced WMD by decreasing inflammation and cell death.
- iNO promoted oligodendrocyte proliferation and maturation, alongside early upregulation of P27kip1 and BDNF.
- Hyperoxia impaired associative learning, but iNO treatment preserved learning abilities comparable to controls.
- iNO demonstrated only minor and transient improvements in BPD markers.
Conclusions:
- Low-dose iNO exhibits specific neuroprotective properties in a preclinical model combining lung and brain injuries relevant to preterm birth complications.
- iNO effectively mitigates white matter damage and preserves cognitive function in neonatal hyperoxia exposure.
- The therapeutic benefits of iNO in this model are primarily neurological, with limited impact on pulmonary aspects of bronchopulmonary dysplasia.
Abstract:
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.
