Cellular Changes Underlying Hyperoxia-Induced Delay of White Matter Development

Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2011; 31(11):4327-44. DOI: 10.1523/JNEUROSCI.3942-10.2011
Source: PubMed


Impaired neurological development in premature infants frequently arises from periventricular white matter injury (PWMI), a condition associated with myelination abnormalities. Recently, exposure to hyperoxia was reported to disrupt myelin formation in neonatal rats. To identify the causes of hyperoxia-induced PWMI, we characterized cellular changes in the white matter (WM) using neonatal wild-type 2-3-cyclic nucleotide 3-phosphodiesterase-enhanced green fluorescent protein (EGFP) and glial fibrillary acidic protein (GFAP)-EGFP transgenic mice exposed to 48 h of 80% oxygen from postnatal day 6 (P6) to P8. Myelin basic protein expression and CC1(+) oligodendroglia decreased after hyperoxia at P8, but returned to control levels during recovery between P12 and P15. At P8, hyperoxia caused apoptosis of NG2(+)O4(-) progenitor cells and reduced NG2(+) cell proliferation. This was followed by restoration of the NG2(+) cell population and increased oligodendrogenesis in the WM after recovery. Despite apparent cellular recovery, diffusion tensor imaging revealed WM deficiencies at P30 and P60. Hyperoxia did not affect survival or proliferation of astrocytes in vivo, but modified GFAP and glutamate-aspartate transporter expression. The rate of [(3)H]-d-aspartic acid uptake in WM tissue was also decreased at P8 and P12. Furthermore, cultured astrocytes exposed to hyperoxia showed a reduced capacity to protect oligodendrocyte progenitor cells against the toxic effects of exogenous glutamate. This effect was prevented by 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide treatment. Our analysis reveals a role for altered glutamate homeostasis in hyperoxia-induced WM damage. Understanding the cellular dynamics and underlying mechanisms involved in hyperoxia-induced PWMI will allow for future targeted therapeutic intervention.

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    • "These secreted factors have different roles in neuronal apoptosis; for example, tumor necrosis factor (TNF) may contribute to injury-induced neuronal apoptosis and play important roles in the pathogenesis of the injury242526. The pre-term period in humans, and early postnatal development in rodents, is a time of active oligodendrogenesis, myelination, and axonal organization in the developing subcortical white matter, and this stage of development is really vulnerable to insults such as hypoxia–ischemia with associated inflammation and oxidative stress27282930. Apart from cell damage, brain ischemia causes neurol o g i c a l d i s t u r b a n c e s . M o r e o v e r, b r a i n -d e r i v e d neurotrophic factor expression is markedly reduced following ischemia in rats and also a rapid loss of synapse formation. "
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    ABSTRACT: The perinatal brainstem is known to be very vulnerable to hypoxic–ischemic events which can lead to deafness, swallowing dysfunction, and defective respiratory control. The aim of the present work was to evaluate the potential neuroprotective effects of nicotine, melatonin, resveratrol, and docosahexaenoic acid on the expression of a panel of genes in the brainstem following hypoxic–ischemic damage. Quantitative PCR was used to examine gene expression 3 and 12 h after the damage, and immunohistochemistry was employed to evaluate neurons, astrocytes, and synaptic vesicles 24 h post insult. We found that the expression of some immediate-early genes, as well as that of inflammatory genes TNF-α, COX2, and caspase 3, was upregulated in response to the insult. Twenty-four hours after the damage, the percentage of NeuN and synaptophysin immunolabeled cells was found to be reduced while GFAP expression was upregulated. No differences were observed in ROS gene expression following treatments.
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    • "Astrocytes react with a biphasic response to hyperoxia, i.e. GFAP and glutamate uptake transporter expression is down-regulated immediately after hyperoxia whereas GFAP significantly increases on P12 (Schmitz et al., 2011). These data suggest that astrocytes rather protect oligodendrocyte precursor cells from glutamate-induced toxicity after hyperoxia than contribute to acute induction of pro-inflammatory cytokines (e.g. "
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    ABSTRACT: Cerebral white matter injury is a leading cause of adverse neurodevelopmental outcome in prematurely born infants involving cognitive deficits in later life. Despite increasing knowledge about the pathophysiology of perinatal brain injury, therapeutic options are limited. In the adult demyelinating disease multiple sclerosis the sphingosine-1-phosphate (S1P) receptor modulating substance fingolimod (FTY720) has beneficial effects. Herein, we evaluated the neuroprotective potential of FTY720 in a neonatal model of oxygen-toxicity, which is associated with hypomyelination and impaired neuro-cognitive outcome.
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    • "Newborn rats exposed to hyperoxia were placed along with their mothers, in a chamber containing 80% O 2 (OxyCycler, BioSpherix, Lacona, NY). It has previously been reported in this rodent model that exposure to 80% oxygen causes a three-to fourfold increase of oxygen tension to values of 155–182 mm Hg (Felderhoff-Mueser et al., 2004; Schmitz et al., 2011). Body weight of P7 pups was similar in both groups, health state and breeding behavior of mothers was not affected by hyperoxia. "

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