Erythropoietin improves motor and cognitive deficit, axonal pathology, and neuroinflammation in a combined model of diffuse traumatic brain injury and hypoxia, in association with upregulation of the erythropoietin receptor
Affiliation
National Trauma Research Institute, Alfred Hospital, Level 4, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, AustraliaDepartment of Surgery, Monash University, Level 4, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, Australia
Department of Physiology, Monash University, Clayton, VIC 3800, Australia
Department of Epidemiology and Preventive Medicine, Monash University, Level 5, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, Australia
Australian New Zealand Intensive Care Research Centre, Level 5, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, Australia
Barrow Neurological Institute, Department of Child Health, University of Arizona, Level 5, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, Australia
Issue Date
2013
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BioMed CentralCitation
Hellewell et al. Journal of Neuroinflammation 2013, 10:156 http://www.jneuroinflammation.com/content/10/1/156Journal
Journal of NeuroinflammationRights
© 2013 Hellewell et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).Collection Information
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.Abstract
BACKGROUND:Diffuse axonal injury is a common consequence of traumatic brain injury (TBI) and often co-occurs with hypoxia, resulting in poor neurological outcome for which there is no current therapy. Here, we investigate the ability of the multifunctional compound erythropoietin (EPO) to provide neuroprotection when administered to rats after diffuse TBI alone or with post-traumatic hypoxia.METHODS:Sprague-Dawley rats were subjected to diffuse traumatic axonal injury (TAI) followed by 30minutes of hypoxic (Hx, 12% O2) or normoxic ventilation, and were administered recombinant human EPO-alpha (5000IU/kg) or saline at 1 and 24hours post-injury. The parameters examined included: 1) behavioural and cognitive deficit using the Rotarod, open field and novel object recognition tests2) axonal pathology (NF-200)
3) callosal degradation (hematoxylin and eosin stain)
3) dendritic loss (MAP2)
4) expression and localisation of the EPO receptor (EpoR)
5) activation/infiltration of microglia/macrophages (CD68) and production of IL-1beta.RESULTS:EPO significantly improved sensorimotor and cognitive recovery when administered to TAI rats with hypoxia (TAI+Hx). A single dose of EPO at 1hour reduced axonal damage in the white matter of TAI+Hx rats at 1day by 60% compared to vehicle. MAP2 was decreased in the lateral septal nucleus of TAI+Hx rats
however, EPO prevented this loss, and maintained MAP2 density over time. EPO administration elicited an early enhanced expression of EpoR 1day after TAI+Hx compared with a 7-day peak in vehicle controls. Furthermore, EPO reduced IL-1beta to sham levels 2hours after TAI+Hx, concomitant to a decrease in CD68 positive cells at 7 and 14days.CONCLUSIONS:When administered EPO, TAI+Hx rats had improved behavioural and cognitive performance, attenuated white matter damage, resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammation, alongside enhanced expression of EpoR. These data provide compelling evidence of EPO's neuroprotective capability. Few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPO's neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic.
EISSN
1742-2094Version
Final published versionAdditional Links
http://www.jneuroinflammation.com/content/10/1/156ae974a485f413a2113503eed53cd6c53
10.1186/1742-2094-10-156
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Except where otherwise noted, this item's license is described as © 2013 Hellewell et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).