title: Inhaled NO prevents hyperoxia-induced white matter damage in neonatal rats.
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.
authors: INSERM, UMR 676, 75019 Paris, France; Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; PremUP foundation, 75014 Paris, France.
authors: Hoa
authors: H
authors: Pham
authors: INSERM, UMR 676, 75019 Paris, France; Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; PremUP foundation, 75014 Paris, France.
authors: Gaelle
authors: G
authors: Vottier
authors: INSERM, UMR 676, 75019 Paris, France; Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; PremUP foundation, 75014 Paris, France.
authors: Julien
authors: J
authors: Pansiot
authors: Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Hôpital Cochin, Service de Physiologie, 75014 Paris, France.
authors: Sy
authors: S
authors: Duong-Quy
authors: INSERM, UMR 676, 75019 Paris, France; Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; PremUP foundation, 75014 Paris, France; University of Leuven, Laboratory of Biological Psychology, Leuven, Belgium.
authors: Bieke
authors: B
authors: Bollen
authors: INSERM, UMR 676, 75019 Paris, France; Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; PremUP foundation, 75014 Paris, France.
authors: Jérémie
authors: J
authors: Dalous
authors: INSERM, UMR 676, 75019 Paris, France; Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; PremUP foundation, 75014 Paris, France.
authors: Jorge
authors: J
authors: Gallego
authors: Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Pediatric emergency department, 75019 Paris, France.
authors: Jean-Christophe
authors: JC
authors: Mercier
authors: Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Hôpital Cochin, Service de Physiologie, 75014 Paris, France.
authors: Anh Tuan
authors: AT
authors: Dinh-Xuan
authors: Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; INSERM, UMR 965, 75010 Paris, France; Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Lariboisière, Physiologie Clinique-Explorations Fonctionnelles, 75010 Paris, France.
authors: Philippe
authors: P
authors: Bonnin
authors: INSERM, UMR 676, 75019 Paris, France; Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; PremUP foundation, 75014 Paris, France.
authors: Christiane
authors: C
authors: Charriaut-Marlangue
authors: INSERM, UMR 676, 75019 Paris, France; Université Paris Diderot, UFR de médecine Denis Diderot, Sorbonne Paris Cité, 75010 Paris, France; PremUP foundation, 75014 Paris, France; Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Neonatal intensive care unit, 75019 Paris, France. Electronic address: olivier.baud@rdb.aphp.fr.
authors: Olivier
authors: O
authors: Baud
mesh_terms: D000280:Administration, Inhalation; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001784:Blood Gas Analysis; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016923:Cell Death; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000860:Hypoxia / Q000150:complications*; D056784:Leukoencephalopathies / Q000209:etiology* / Q000517:prevention & control*; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009569:Nitric Oxide / Q000008:administration & dosage*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; C019277:brain-derived growth factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D009569:Nitric Oxide
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