Deleterious Effect of Hyperoxia at Birth on White Matter Damage in the Newborn Rat

INSERM, AVENIR R05230HS (U676), Université Paris 7, Faculté de Médecine Denis Diderot, IFR 02, Paris, France.
Developmental Neuroscience (Impact Factor: 2.7). 06/2011; 33(3-4):261-9. DOI: 10.1159/000327245
Source: PubMed

ABSTRACT White matter damage (WMD) remains the leading cause of cerebral palsy in children born prematurely. The release of an excessive amount of reactive oxygen species is recognized as a risk factor for WMD. We hypothesize that free radical injury during reoxygenation at birth may be harmful to the immature white matter and may underlie, at least in part, the pathogenesis of WMD. We tested this hypothesis in rat pups delivered from normoxic pregnant rats, and by investigating an animal model based on protracted antenatal hypoxia in the pregnant rat and mimicking the main features of human WMD in rat pups. From embryonic day (E)5 to E21, the pregnant rats were placed in a chamber supplied with a gas mixture that either induced hypoxia (FiO(2) = 10%) or maintained normoxia (FiO(2) = 21%). On E21, the dams were removed from the chamber and housed under either normoxia (FiO(2) = 21%), hyperoxia (FiO(2) = 60%) or slowly reoxygenated (FiO(2) from 15% at E21 to 21% at postnatal day 7). Postnatal hyperoxia was associated with a significantly increased density of activated microglial cells (+105%) and TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling)-positive cells (+85%) within the developing white matter. Myelin content (-31%) and mature oligodendrocyte density (-37%) in the normal developing white matter were significantly decreased by postnatal hyperoxia. Postnatal hyperoxia significantly potentiated the myelination delay and oligodendroglial dysmaturation induced by antenatal hypoxia. In contrast, progressive reoxygenation at birth did not induce any change in white matter inflammation, myelination and cell death as compared with normoxic controls, and prevented most of the WMD observed following antenatal hypoxia. This study demonstrates a deleterious effect of hyperoxia at birth on the developing white matter in normal rat pups. Postnatal hyperoxia worsened the WMD induced by antenatal hypoxia. Hyperoxia at birth should be avoided in preterm infants at risk of WMD.

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Available from: Pierre Gressens, Jun 07, 2015
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    • "Both intermittent and continuous neonatal hypoxia reduce long-term myelination and induce angiogenesis in the rat brain [10,23]. Furthermore, neonatal hyperoxia causes microvascular degeneration in grey matter [24] and maturation-dependent cell death in white matter [25,26]. It is conceivable that, both in the retina and brain, fluctuations between high and low oxygen levels disturb the coordinated formation of the neurovascular unit in a period of major growth and differentiation in both organs. "
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    ABSTRACT: Background Neonatal intermittent hyperoxia-hypoxia (IHH) is involved in the pathogenesis of retinopathy of prematurity. Whether similar oxygen fluctuations will create pathological changes in the grey and white matter of the brain is unknown. Methods From birth until postnatal day 14 (P14), two litters (total n = 22) were reared in IHH: hyperoxia (50% O2) interrupted by three consecutive two-minute episodes of hypoxia (12% O2) every sixth hour. Controls (n = 8) were reared in room-air (20.9% O2). Longitudinal MRI (Diffusion Tensor Imaging and T2-mapping) was performed on P14 and P28 and retinal and brain tissue were examined for histopathological changes. Long-term neurodevelopment was assessed on P20 and P27. Results Mean, radial and axial diffusivity were higher in white matter of IHH versus controls at P14 (p < 0.04), while fractional anisotropy (FA) was lower in the hippocampal fimbria and tended to be lower in corpus callosum (p = 0.08) and external capsule (p = 0.05). White matter diffusivity in IHH was similar to controls at P28. Higher cortical vessel density (p = 0.005) was observed at P14. Cortical and thalamic T2-relaxation time and mean diffusivity were higher in the IHH group at P14 (p ≤ 0.03), and albumin leakage was present at P28. Rats in the IHH group ran for a longer time on a Rotarod than the control group (p ≤ 0.005). Pups with lower bodyweight had more severe MRI alterations and albumin leakage. Conclusion IHH led to subtle reversible changes in brain white matter diffusivity, grey matter water content and vascular density. However, alterations in blood-brain barrier permeability may point to long-term effects. The changes seen after IHH exposure were more severe in animals with lower bodyweight and future studies should aim at exploring possible interactions between IHH and growth restriction.
    PLoS ONE 12/2013; 8(12):e84109. DOI:10.1371/journal.pone.0084109 · 3.23 Impact Factor
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    • "For example, using a neonatal rat model of hypoxic-ischemic brain injury, Back and colleagues found that the white matter injury involved apoptotic death of the late OPCs (oligodendrocyte progenitor cells) (Back et al., 2001, 2002). Late OPCs also were found to be vulnerable to cell death in other models of neonatal white matter injury (Vottier et al., 2011; Falahati et al., 2013). Oligodendrocyte progenitors are especially vulnerable to increased levels of glutamate, which has been implicated in white matter damage after neonatal H–I (hypoxia–ischemia), spinal cord injury and multiple sclerosis (Petito et al., 1998; Ness et al., 2001; Park et al., 2004). "
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    ABSTRACT: Oligodendrocyte progenitor (OPC) cell death contributes significantly to the pathology and functional deficits following hypoxic-ischemic injury in the immature brain and to deficits resulting from demyelinating diseases, trauma and degenerative disorders in the adult CNS. Glutamate toxicity is a major cause of oligodendroglial death in diverse CNS disorders, and previous studies have demonstrated that AMPA/kainate receptors require the pro-apoptotic protein Bax in OPCs undergoing apoptosis. The goal of this study was to define the pro-apoptotic and anti-apoptotic effectors that regulate Bax in healthy OPCs and after exposure to excess glutamate in vitro and following hypoxia-ischemia in the immature rat brain. We show that Bax associates with a truncated form of Bid, a BH3-only domain protein, subsequent to glutamate treatment. Furthermore, glutamate exposure reduces Bax association with the anti-apoptotic Bcl family member, Bcl-xL. Cell fractionation studies demonstrated that both Bax and Bid translocate from the cytoplasm to mitochondria during the early stages of cell death consistent with a role for Bid as an activator, whereas Bcl-xL which normally complexes with both Bax and Bid, disassociates from these complexes when OPCs are exposed to excess glutamate. Bax remained un-activated in the presence of insulin-like growth factor-I, and the Bcl-xL complexes were protected. Our data similarly demonstrate loss of Bcl-xL:Bax association in white matter following H-I and implicate active Bad in Bax-mediated OPC death. To identify other Bax binding partners, we used proteomics and identified cofilin as a Bax-associated protein. Cofilin and Bax associated in healthy OPCs, whereas the Bax:cofilin association was disrupted during glutamate-induced OPC apoptosis.
    ASN Neuro 11/2013; 5(5). DOI:10.1042/AN20130027 · 4.02 Impact Factor
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    • "Therefore, the higher FA accompanied by lower MD mean that the motion of water diffusion is more restricted and more directional. A number of researches indicated that oligodendroglial loss [15], [55] and myelination delay [56] caused by acute exposed to high concentration of oxygen may be related to WM damage. In another aspect, neurogenesis induced by low-to-moderate level hyperoxia has been proved in vitro and vivo observations [19]. "
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    ABSTRACT: The present study aimed to investigate structural modulation of brain by high level of oxygen during its peak period of development. Voxel-based morphometry analysis of gray matter (GM) and white matter (WM) volumes and Tract-Based Spatial Statistics analysis of WM fractional anisotropy (FA) and mean diffusion (MD) based on MRI images were carried out on 21 Tibetan adolencents (15-18 years), who were born and raised in Qinghai-Tibetan Plateau (2900-4700 m) and have lived at sea level (SL) in the last 4 years. The control group consisted of matched Tibetan adolescents born and raised at high altitude all the time. SL immigrants had increased GM volume in the left insula, left inferior parietal gyrus, and right superior parietal gyrus and decreased GM in the left precentral cortex and multiple sites in cerebellar cortex (left lobule 8, bilateral lobule 6 and crus 1/2). Decreased WM volume was found in the right superior frontal gyrus in SL immigrants. SL immigrants had higher FA and lower MD at multiple sites of WM tracts. Moreover, we detected changes in ventilation and circulation. GM volume in cerebellum lobule 8 positively correlated with diastolic pressure, while GM volume in insula positively correlated vital capacity and hypoxic ventilatory response. Our finding indicate that the structural modulations of GM by high level of oxygen during its peak period of development are related to respiratory and circulatory regulations, while the modulation in WM mainly exhibits an enhancement in myelin maturation.
    PLoS ONE 07/2013; 8(7):e67803. DOI:10.1371/journal.pone.0067803 · 3.23 Impact Factor
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