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

Persistent Link:
http://hdl.handle.net/10150/610192
Title:
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
Author:
Hellewell, Sarah; Yan, Edwin; Alwis, Dasuni; Bye, Nicole; Morganti-Kossmann, M.
Affiliation:
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
Issue Date:
2013
Publisher:
BioMed Central
Citation:
Hellewell et al. Journal of Neuroinflammation 2013, 10:156 http://www.jneuroinflammation.com/content/10/1/156
Journal:
Journal of Neuroinflammation
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)
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 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.
EISSN:
1742-2094
DOI:
10.1186/1742-2094-10-156
Keywords:
Traumatic brain injury (TBI); Traumatic axonal injury; Hypoxia; Erythropoietin; EPO; Neuroprotection
Version:
Final published version
Additional Links:
http://www.jneuroinflammation.com/content/10/1/156

Full metadata record

DC FieldValue Language
dc.contributor.authorHellewell, Sarahen
dc.contributor.authorYan, Edwinen
dc.contributor.authorAlwis, Dasunien
dc.contributor.authorBye, Nicoleen
dc.contributor.authorMorganti-Kossmann, M.en
dc.date.accessioned2016-05-20T09:00:42Z-
dc.date.available2016-05-20T09:00:42Z-
dc.date.issued2013en
dc.identifier.citationHellewell et al. Journal of Neuroinflammation 2013, 10:156 http://www.jneuroinflammation.com/content/10/1/156en
dc.identifier.doi10.1186/1742-2094-10-156en
dc.identifier.urihttp://hdl.handle.net/10150/610192-
dc.description.abstractBACKGROUND: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 testsen
dc.description.abstract2) axonal pathology (NF-200)en
dc.description.abstract3) callosal degradation (hematoxylin and eosin stain)en
dc.description.abstract3) dendritic loss (MAP2)en
dc.description.abstract4) expression and localisation of the EPO receptor (EpoR)en
dc.description.abstract5) 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 ratsen
dc.description.abstracthowever, 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.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://www.jneuroinflammation.com/content/10/1/156en
dc.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)en
dc.subjectTraumatic brain injury (TBI)en
dc.subjectTraumatic axonal injuryen
dc.subjectHypoxiaen
dc.subjectErythropoietinen
dc.subjectEPOen
dc.subjectNeuroprotectionen
dc.titleErythropoietin 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 receptoren
dc.typeArticleen
dc.identifier.eissn1742-2094en
dc.contributor.departmentNational Trauma Research Institute, Alfred Hospital, Level 4, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, Australiaen
dc.contributor.departmentDepartment of Surgery, Monash University, Level 4, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, Australiaen
dc.contributor.departmentDepartment of Physiology, Monash University, Clayton, VIC 3800, Australiaen
dc.contributor.departmentDepartment of Epidemiology and Preventive Medicine, Monash University, Level 5, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, Australiaen
dc.contributor.departmentAustralian New Zealand Intensive Care Research Centre, Level 5, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, Australiaen
dc.contributor.departmentBarrow Neurological Institute, Department of Child Health, University of Arizona, Level 5, Burnet Tower, 89 Commercial Road, Melbourne, VIC 3000, Australiaen
dc.identifier.journalJournal of Neuroinflammationen
dc.description.collectioninformationThis 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.en
dc.eprint.versionFinal published versionen
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