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

Pham, Hoa; Vottier, G.; Pansiot, Julien; Duong‐Quy, Sy; Bollen, Bieke; Dalous, Jérémie; Gallego, Jorge; Mercier, Jean-Christophe; Dinh-Xuan, Anh Tuan; Bonnin, Philippe; Charriaut‐Marlangue, Christiane; Baud, Olivier

doi:10.1016/j.expneurol.2013.11.025

Cited by 35 publications

(37 citation statements)

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“…This effect was only transient and no longer observed at P3 and P7 (brain concentrations have been found below the detection limit at these time points with and without iNO). These data were consistent with the changes of NO concentration detected by the voltammetric method in the developing brain following iNO, which we have previously reported [11]. …”

Section: Resultssupporting

confidence: 80%

“…For brain immunohistochemistry at P7, coronal sections (+1.44 to -0.48 mm from bregma) were selected and processed as previously described [11]. In each experimental group, we studied 7-8 pups in three separate experiments.…”

Section: Methodsmentioning

confidence: 99%

“…However, several lines of evidence demonstrate that low doses of iNO not only act locally on the pulmonary vasculature but also have remote effects on the developing brain under basal or pathological conditions by modulating white matter maturation, inflammation and subsequent brain repair [8]. Indeed, we recently reported that the NO pathway is able to promote oligodendroglial maturation, myelination and neuroprotection in preclinical models of neonatal stroke and white matter damage induced by postnatal hyperoxia or excitotoxic insult [9,10,11,12]. Several other reports have demonstrated that iNO is associated with significant neuroprotection in preclinical models of adult brain damage [13,14,15].…”

Section: Introductionmentioning

confidence: 99%

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Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat

Duy¹,

Pham²,

Pansiot³

et al. 2015

Dev Neurosci

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Several lines of evidence demonstrate that inhaled nitric oxide (iNO) not only acts locally on the pulmonary vasculature but also has remote effects on the mature and developing brain under basal or pathological conditions by modulating cerebral blood flow and microvascularization, white matter maturation, inflammation, and subsequent brain repair. Previously, consistent studies demonstrated that increased levels of guanosine 3′,5′ cyclic monophosphate (cGMP), the main effector of biological effect induced by nitric oxide (NO), significantly augment proliferation and neuronal differentiation of adult neural progenitor cells (NPCs). In the present study, we ask the question whether iNO could promote the proliferation of NPCs in the uninjured developing brain. We first reported that iNO exposure at a concentration of 20 ppm during the first 7 days of life was associated with a significant but transient elevation of brain cGMP concentration 2 h after the onset of iNO exposure and a subsequent increase in myelin content of the developing white matter at postnatal day (P) 10. Using BrDu labelling and colabelling with specific cell-type markers we found that iNO exposure of rat pups results in an increased NPC proliferation in several layers of the subventricular zone (SVZ) at both early (30 h) and late (P7) time points. These proliferating NPCs were found to be sustainably viable and subsequently differentiated into oligodendroglial cells in the developing white matter and cortex. We also found that NG2 immunoreactivity around vessel walls, labeling pericyte cells, was increased in NO-exposed rat pups in the periventricular SVZ. In conclusion, iNO appears to act on oligodendrocyte progenitor cells, leading to increased density of mature oligodendrocytes and myelin content in the immature rat brain.

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Section: Resultssupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat

Duy¹,

Pham²,

Pansiot³

et al. 2015

Dev Neurosci

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“…In addition to the lung injury known to occur after prolonged exposure to hyperoxia (90% oxygen for 14 d), our data revealed simultaneous hyperoxic brain injury, shown by a retardation in brain weight gain, transiently increased carbonylated protein, reduced MBP, and an increased TUNEL-positive cells and caspase-3 expression, without changes in inflammatory cytokine levels, the number of activated microglia, and superoxide dismutase activity. These observations indicate that the newborn rat model used in this study appropriately simulates the clinical conditions of BPD with associated brain injury in premature infants (4,16).…”

Section: Discussionmentioning

confidence: 88%

Intratracheal transplantation of mesenchymal stem cells simultaneously attenuates both lung and brain injuries in hyperoxic newborn rats

et al. 2016

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Background: Bronchopulmonary dysplasia is an independent risk factor for adverse neurodevelopmental outcomes in premature infants. We investigated whether attenuation of hyperoxic lung injury with intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells (MSCs) could simultaneously mitigate brain damage in neonatal rats. Methods: Newborn Sprague-Dawley rats were exposed to hyperoxia or normoxia conditions for 14 d. MSCs (5 × 10 5 cells) were transplanted intratracheally at postnatal day (P) 5. At P14, lungs and brains were harvested for histological and biochemical analyses. results: Hyperoxic lung injuries, such as impaired alveolarization evident from increased mean linear intercept (MLI) and elevated inflammatory cytokine levels were significantly alleviated with MSC transplantation. Hyperoxia decreased brain weight, increased brain cell death, and induced hypomyelination. MSC transplantation significantly ameliorated hyperoxiainduced increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the dentate gyrus and reduced myelin basic protein. In correlation analyses, brain weight and myelin basic protein (MBP) were significantly inversely correlated with lung MLI and inflammatory cytokines, while TUNEL-positive brain cell number showed a significant positive correlation with lung MLI. conclusion: Despite no significant improvement in shortterm neurofunctional outcome, intratracheal transplantation of MSCs simultaneously attenuated hyperoxic lung and brain injuries in neonatal rats, with the extent of such attenuation being closely linked in the two tissues. Bronchopulmonary dysplasia (BPD), a chronic lung disease that occurs in premature infants receiving prolonged ventilator support and oxygen supplementation, is associated with an increased risk of long-term neurodevelopmental impairments (1). Despite its limited predictive value, some clinical studies have also identified BPD as an independent risk factor for the development of neurofunctional deficits in premature infants, including cerebral palsy and developmental retardation, even in the absence of catastrophic brain injuries such as intraventricular hemorrhage and hypoxic-ischemic encephalopathy (1-3). No specific or effective treatment is currently available for the preterm infant brain. However, as indicated by evidence from Pham et al. (4), the close association between BPD and brain injury suggests that pulmo-protective therapies might also be neuroprotective in premature infants.Recently, we reported that intratracheal xenotransplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) significantly attenuated hyperoxiainduced lung injuries in immune-competent newborn rats (5-7). Furthermore, in a phase I clinical trial, we showed that intratracheal transplantation of allogenic human UCB-derived MSCs in very preterm infants is safe and feasible (8). However, beyond its pulmo-protective properties, the potential neuroprotective effects of intratracheal...

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“…Transcript levels of eNOS in lung tissues were determined by quantitative RT-PCR using a LightCycler® 480 System (Roche Applied Biosystems, Foster City, CA, USA) and normalised to hypoxanthine-guanine phosphoribosyltransferase (HPRT) as previously described [16]. …”

Section: Methodsmentioning

confidence: 99%

Inhaled nitric oxide decreases pulmonary endothelial nitric oxide synthase expression and activity in normal newborn rat lungs

et al. 2016

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Inhaled nitric oxide (iNO) is commonly used in the treatment of very ill pre-term newborns. Previous studies showed that exogenous NO could affect endothelial NO synthase (eNOS) activity and expression in vascular endothelial cell cultures or adult rat models, but this has never been fully described in newborn rat lungs. We therefore aimed to assess the effects of iNO on eNOS expression and activity in newborn rats.Rat pups, post-natal day (P) 0 to P7, and their dams were placed in a chamber containing NO at 5 ppm (iNO-5 ppm group) or 20 ppm (iNO-20 ppm group), or in room air (control group). Rat pups were sacrificed at P7 and P14 for evaluation of lung eNOS expression and activity.At P7, eNOS protein expression in total lung lysates, in bronchial and arterial sections, was significantly decreased in the iNO-20 ppm versus control group. At P14, eNOS expression was comparable among all three groups. The amounts of eNOS mRNA significantly differed at P7 between the iNO-20 ppm and control groups. NOS activity decreased in the iNO-20 ppm group at P7 and returned to normal levels at P14. There was an imbalance between superoxide dismutase and NOS activities in the iNO-20 ppm group at P7.Inhalation of NO at 20 ppm early after birth decreases eNOS gene transcription, protein expression and enzyme activity. This decrease might account for the rebound phenomenon observed in patients treated with iNO.

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

Cited by 35 publications

References 46 publications

Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat

Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat

Intratracheal transplantation of mesenchymal stem cells simultaneously attenuates both lung and brain injuries in hyperoxic newborn rats

Inhaled nitric oxide decreases pulmonary endothelial nitric oxide synthase expression and activity in normal newborn rat lungs

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