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, 2016, 9247493

Erythropoietin Restores Long-Term Neurocognitive Function Involving Mechanisms of Neuronal Plasticity in a Model of Hyperoxia-Induced Preterm Brain Injury

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Erythropoietin Restores Long-Term Neurocognitive Function Involving Mechanisms of Neuronal Plasticity in a Model of Hyperoxia-Induced Preterm Brain Injury

Daniela Hoeber et al. Oxid Med Cell Longev.

Abstract

Cerebral white and grey matter injury is the leading cause of an adverse neurodevelopmental outcome in prematurely born infants. High oxygen concentrations have been shown to contribute to the pathogenesis of neonatal brain damage. Here, we focused on motor-cognitive outcome up to the adolescent and adult age in an experimental model of preterm brain injury. In search of the putative mechanisms of action we evaluated oligodendrocyte degeneration, myelination, and modulation of synaptic plasticity-related molecules. A single dose of erythropoietin (20,000 IU/kg) at the onset of hyperoxia (24 hours, 80% oxygen) in 6-day-old Wistar rats improved long-lasting neurocognitive development up to the adolescent and adult stage. Analysis of white matter structures revealed a reduction of acute oligodendrocyte degeneration. However, erythropoietin did not influence hypomyelination occurring a few days after injury or long-term microstructural white matter abnormalities detected in adult animals. Erythropoietin administration reverted hyperoxia-induced reduction of neuronal plasticity-related mRNA expression up to four months after injury. Thus, our findings highlight the importance of erythropoietin as a neuroregenerative treatment option in neonatal brain injury, leading to improved memory function in adolescent and adult rats which may be linked to increased neuronal network connectivity.

Figures

Figure 1
Figure 1
Erythropoietin improved cognitive function following neonatal hyperoxia. Motor-cognitive development was assessed by open field, novel object recognition, and Barnes maze starting at P30 (adolescent) and P90 (adult) after exposure to neonatal normoxia (21% oxygen (21%)) or hyperoxia (24 h, 80% oxygen (80%)) at P6 combined with i.p. administration of normal saline or 20,000 IU/kg Epo. (a) To test general motor activity animals were placed into the open field maze for 10 minutes. Movement of animals was tracked automatically by the software through three-point detection and the centre of the animals was analysed. Motor activity was expressed by the mean velocity and the total distance. (b) Cognitive function was assessed in the novel object recognition task presented as the exploration time at the novel object (N) versus familiar objects (F1 and F2). (c) Memory function was determined in the Barnes maze test expressed as the latency to find the trained escape hole after a 3-day training period. n = 8–10 rats/group. p < 0.05, ∗∗ p < 0.01, and ∗∗∗ p < 0.001.
Figure 2
Figure 2
Erythropoietin ameliorates oligodendrocyte degeneration but not hyperoxia-mediated hypomyelination. (a) Oligodendrocyte degeneration was determined in brain sections from P7 rats that were exposed to either normoxia (21% oxygen (21%)) or hyperoxia (24 h, 80% oxygen (80%)) at P6 and treated with normal saline or 20,000 IU/kg Epo. Oligodendrocyte degeneration was determined by immunohistochemical TUNEL (green)/Olig2 (red) and DAPI (not depicted) costaining (positive counted cells appear yellow and are marked by arrows). Scale  bar = 50 μm, n = 8–10 rats/group. (b) Myelin basic protein (MBP) expression was analysed 4 days after hyperoxia in protein lysates of complete hemispheres (excluding cerebellum). n = 8–10 rats/group. ∗∗ p < 0.01, ∗∗∗ p < 0.001.
Figure 3
Figure 3
Long-term white matter microstructural development is not improved by a single injection of erythropoietin. (a) Representative T2W images (b0), fractional anisotropy (FA) maps, and direction encoded colour maps (DEC) of a P125 control rat (21%) derived from diffusion tensor imaging showing the different levels used for quantitative analysis. Corpus callosum (CC) and external capsule (EC) are displayed on the DEC. Diffusivity values of radial diffusivity (D ), axial diffusivity (D //), mean diffusivity (MD), and fractional anisotropy in corpus callosum (b) and external capsule (c) determined by diffusion tensor imaging out of rats exposed to normoxia (21% oxygen (21%)) or hyperoxia (24 h, 80% oxygen (80%)) at P6 and treated with normal saline or 20,000 IU/kg Epo. n = 6 rats/group. p < 0.05, ∗∗ p < 0.01.
Figure 4
Figure 4
Erythropoietin restores plasticity-related genes following neonatal hyperoxia. Synaptophysin (Syp), neuregulin-1 (Nrg1), and neuropilin-1 (Nrp1) mRNA expression in hemispheres of (a) P7, (b) P11, and (c) P125 rats exposed to either normoxia (21% oxygen (21%)) or hyperoxia (24 h, 80% oxygen (80%)) at P6 and treated with normal saline or 20,000 IU/kg Epo i.p. n = 4–8 rats/group. p < 0.05, ∗∗ p < 0.01, and ∗∗∗ p < 0.001.

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