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 tests / 2) 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.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/610192 |
| Date | January 2013 |
| Creators | Hellewell, Sarah, Yan, Edwin, Alwis, Dasuni, Bye, Nicole, Morganti-Kossmann, M. |
| Contributors | National Trauma Research Institute, Alfred Hospital, Level 4, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, Australia, Department 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 |
| Publisher | BioMed Central |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | © 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) |
| Relation | http://www.jneuroinflammation.com/content/10/1/156 |
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