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

Pham, Hoa; Duy, An Phan; Pansiot, Julien; Bollen, Bieke; Gallego, Jorge; Charriaut‐Marlangue, Christiane; Baud, Olivier

doi:10.1038/pr.2015.4

Cited by 36 publications

(47 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These abnormal patterns may reflect abnormal neuronal activity and myelination and therefore abnormal functionality in the IUGR brain. These abnormal neuronal and/or white matter patterns have also been demonstrated in small animal models of IUGR (Wixey et al, 2016) with loss of oligodendrocytes, decreased proliferation and differentiation reported (Mazur et al, 2010;Olivier et al, 2005;Pham et al, 2015;Tolcos et al, 2011). Yet some studies show postnatal restoration of white matter (Olivier et al, 2007;Reid et al, 2012;Tolcos et al, 2011).…”

Section: Discussionmentioning

confidence: 91%

GABA_A receptor expression and white matter disruption in intrauterine growth restricted piglets

Kalanjati

Wixey

Miller

et al. 2017

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

Intrauterine growth restriction (IUGR) is one of the most common causes of perinatal mortality and morbidity. White matter and neuronal injury are major pathophysiological features of the IUGR neonatal brain. GABA (γ-aminobutyric acid type A) receptors have been shown to play a role in oligodendrocyte differentiation and proliferation in the neonatal brain and may be a key factor in white matter injury and myelination in IUGR neonates. Whether there are impairments to the GABAergic system and neuronal cytoskeleton in IUGR brain has yet to be elucidated. This study aims to examine GABA receptor α and α subunit protein expression and distribution in parietal cortex and hippocampus of the IUGR piglet at four different ages (term=115d - days gestational age), 100d, 104d, birth (postnatal day 0-P0) and P7 and to examine neuronal and myelination patterns. Significant alterations to GABA receptor α and α protein expression levels were observed in the IUGR piglet brain of P7 IUGR piglets with significantly greater α expression compared to α expression in the hippocampus while there was virtually no difference between the two subunits in the parietal cortex. However a significantly lower α/α ratio was evident in P7 IUGR cortex when compared with P7 NG cortex. Neuronal somatodendrites studied using MAP2 immunohistochemistry showed reduced and disrupted somatodendrites while MBP immunolabelling showed loss of axonal fibres from gestational day 104d through to P7. These findings provide insights into the effects of IUGR on the development of the GABA system, altered developmental maturation of GABA receptor subunit expression in the IUGR brain may influence myelination and may partly explain the cognitive disabilities observed in IUGR. Understanding the mechanisms behind grey and white matter injury in the IUGR infant is essential to identifying targets for treatments to improve long-term outcomes for IUGR infants.

show abstract

Section: Discussionmentioning

confidence: 91%

GABA_A receptor expression and white matter disruption in intrauterine growth restricted piglets

Kalanjati

Wixey

Miller

et al. 2017

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

show abstract

“…On imaging, the FGR infant brain shows reduced total brain volume and grey matter volume [11] , and reduced hippocampal and cerebellar volume [13][14][15][16] , which might be contributed by neuronal cell loss [17] or delayed cellular complexity. Animal models of FGR, predominantly late-onset FGR, demonstrate white matter deficits as evidenced by delayed myelination [18,19] , hypomyelination, and reduced total white matter volume [20][21][22] .…”

Section: Introductionmentioning

confidence: 99%

Early- versus Late-Onset Fetal Growth Restriction Differentially Affects the Development of the Fetal Sheep Brain

et al. 2017

View full text Add to dashboard Cite

Fetal growth restriction (FGR) is a common complication of pregnancy, principally caused by suboptimal placental function, and is associated with high rates of perinatal mortality and morbidity. Clinical studies suggest that the time of onset of placental insufficiency is an important contributor towards the neurodevelopmental impairments that are evident in children who had FGR. It is however currently unknown how early-onset and late-onset FGR differentially affect brain development. The aim of this study was to examine neuropathology in early-onset and late-onset FGR fetal sheep and to determine whether they differentially alter brain development. We induced placental insufficiency and FGR via single umbilical artery ligation at either 88 days (early-onset) or 105 days (late-onset) of fetal sheep gestation (term is approx. 147 days), reflecting a period of rapid white matter brain development. Fetal blood samples were collected for the first 10 days after surgery, and all fetuses were sacrificed at 125 days' gestation for brain collection and subsequent histopathology. Our results show that early-onset FGR fetuses became progressively hypoxic over the first 10 days after onset of placental insufficiency, whereas late-onset FGR fetuses were significantly hypoxic compared to controls from day 1 after onset of placental insufficiency (SaO₂ 46.7 ± 7.4 vs. 65.7 ± 3.9%, respectively, p = 0.03). Compared to control brains, early-onset FGR brains showed widespread white matter injury, with a reduction in both CNPase-positive and MBP-positive density of staining in the periventricular white matter (PVWM), subcortical white matter, intragyral white matter (IGWM), subventricular zone (SVZ), and external capsule (p < 0.05 for all). Total oligodendrocyte lineage cell counts (Olig-2-positive) did not differ across groups, but mature oligodendrocytes (MBP-positive) were reduced, and neuroinflammation was evident in early-onset FGR brains with reactive astrogliosis (GFAP-positive) in the IGWM and cortex (p < 0.05), together with an increased number of Iba-1-positive activated microglia in the PVWM, SVZ, and cortex (p < 0.05). Late-onset FGR was associated with a widespread reduction of CNPase-positive myelin expression (p < 0.05) and a reduced number of mature oligodendrocytes in all white matter regions examined (p < 0.05). NeuN-positive neuronal cell counts in the cortex were not different across groups; however, the morphology of neuronal cells was different in response to placental insufficiency, most notable in the early-onset FGR fetuses, but it was late-onset FGR that induced caspase-3-positive apoptosis within the cortex. This study demonstrates that early-onset FGR is associated with more widespread white matter injury and neuroinflammation; however, both early- and late-onset FGR are associated with complex patterns of white and grey matter injury. These results indicate that it is the timing of the onset of fetal compromise relative to brain development that principally mediates altered ...

show abstract

“…Interestingly, Sildenafil also reduced apoptosis, astrocytosis, and microgliosis [285]. Additionally, it has been shown that inhaling NO antagonizes hyperoxia-induced white matter damage, mitigates induced-stroke-associated brain damage, enhances CNS myelination, and promotes neural progenitor proliferation in various neonatal models [285,286,287,288,289]. …”

Section: The Utility Of Pde Inhibitors For Neuroprotection and Neumentioning

confidence: 99%

Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair

Knott

Assi

Rao

et al. 2017

IJMS

View full text Add to dashboard Cite

A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic.

show abstract

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

Abstract: This study provides new evidence that iNO could be effective in preventing brain damage and/or enhancing repair of the developing brain.

Cited by 36 publications

References 38 publications

GABA_A receptor expression and white matter disruption in intrauterine growth restricted piglets

GABA_A receptor expression and white matter disruption in intrauterine growth restricted piglets

Early- versus Late-Onset Fetal Growth Restriction Differentially Affects the Development of the Fetal Sheep Brain

Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair

Contact Info

Product

Resources

About

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

Abstract: This study provides new evidence that iNO could be effective in preventing brain damage and/or enhancing repair of the developing brain.

Cited by 36 publications

References 38 publications

GABAA receptor expression and white matter disruption in intrauterine growth restricted piglets

GABAA receptor expression and white matter disruption in intrauterine growth restricted piglets

Early- versus Late-Onset Fetal Growth Restriction Differentially Affects the Development of the Fetal Sheep Brain

Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair

Contact Info

Product

Resources

About

GABA_A receptor expression and white matter disruption in intrauterine growth restricted piglets

GABA_A receptor expression and white matter disruption in intrauterine growth restricted piglets