Deleterious Effect of Hyperoxia at Birth on White Matter Damage in the Newborn Rat
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.
SourceAvailable from: Christoph Bührer[Show abstract] [Hide abstract]
ABSTRACT: White matter disease in preterm infants comes along with focal destructions or with diffuse myelination disturbance. Recent experimental work with transgenic mice paves the way for a unifying molecular model for both types of brain injury, placing oxygen sensing by oligodendrocyte precursor cells (OPCs) at the center stage. Mice genetically altered to mimic high local oxygen tension in oligodendroglia lineage cells (via deletion of hypoxia-inducible factor, HIF) develop white matter disease resembling cystic periventricular leukomalacia within the first 7 days of life. Mice in which local hypoxia is mimicked in oligodendroglial cells (via genetic inhibition of HIF decay) display arrested OPC maturation and subsequent hypomyelination, reminiscent of the diffuse white matter disease observed in preterm infants and infants with congenital heart disease. These recent experimental findings on oxygen sensing and myelination are awaiting integration into a clinical framework. Gene regulation in response to hyperoxia or hypoxia, rather than oxidative stress, may be an important mechanism underlying neonatal white matter disease.Frontiers in Pediatrics 01/2014; 2:143. DOI:10.3389/fped.2014.00143
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ABSTRACT: Oligodendrocyte progenitor cells (OPCs) are susceptible to perinatal hypoxia ischemia brain damage (HIBD), which results in infant cerebral palsy due to the effects on myelination. The origin of OPC vulnerability in HIBD, however, remains controversial. In this study, we defined the HIBD punctate lesions by MRI diffuse excessive high signal intensity (DEHSI) in postnatal 7-day rats. The electrophysiological functional properties of OPCs in HIBD were recorded by patch clamp in acute cerebral cortex slices. The slices were intracellularly injected with Lucifer yellow and immunohistochemically labeled with NG2 antibody to identify local OPCs. Passive membrane properties and K(+) channel functions in OPCs were analyzed to estimate the onset of vulnerability in HIBD. The resting membrane potential (RMP), membrane resistance (Rin) and membrane capacitance (Cm) of OPCs were increased both in the grey and white matter of the cerebral cortex. OPCs in both the grey and white matter exhibited voltage-dependent K(+) currents, which consisted of the initiated rectified potassium currents (IA) and the sustained rectified currents (IK). The significant alternation in membrane resistance was influenced by the diversity of potassium channel kinetics. These findings suggest that the rectification of IA and IK channels may play a significant role in OPC vulnerability in HIBD.Journal of Neurophysiology 10/2014; 113(2):jn.00144.2014. DOI:10.1152/jn.00144.2014 · 3.04 Impact Factor
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ABSTRACT: Spastic cerebral palsy is generally considered to result from cerebral cortical or pyramidal tract damage. Here, we precisely targeted the left pyramidal tract of 2-month-old Sprague-Dawley rats placed on a stereotaxic instrument under intraperitoneal anesthesia. Based on the rat brain stereotaxic map, a 1-mm hole was made 10 mm posterior to bregma and 0.8 mm left of sagittal suture. A microsyringe was inserted perpendicularly to the surface of the brain to a depth of 9.7 mm, and 15 μL of ethanol was slowly injected to establish a rat model of spastic cerebral palsy. After modeling, the rats appeared to have necrotic voids in the pyramidal tract and exhibited typical signs and symptoms of flexion spasms that lasted for a long period of time. These findings indicate that this is an effective and easy method of establishing a rat model of spastic cerebral palsy with good re-producibility. Ethanol as a chemical ablation agent specifically and thoroughly damages the pyramidal tract, and therefore, the animals display flexion spasms, which are a typical symptom of the disease.Neural Regeneration Research 12/2013; 8(34):3255-62. DOI:10.3969/j.issn.1673-5374.2013.34.010 · 0.23 Impact Factor