title: Erythropoietin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.
abstract: Experimental studies targeting traumatic brain injury (TBI) have reported that erythropoietin (EPO) is an endogenous neuroprotectant in multiple models. In addition to its neuroprotective effects, it has also been shown to enhance reparative processes including angiogenesis and neurogenesis. Based on compelling pre-clinical data, EPO was tested by the Operation Brain Trauma Therapy (OBTT) consortium to evaluate therapeutic potential in multiple TBI models along with biomarker assessments. Based on the pre-clinical TBI literature, two doses of EPO (5000 and 10,000 IU/kg) were tested given at 15 min after moderate fluid percussion brain injury (FPI), controlled cortical impact (CCI), or penetrating ballistic-like brain injury (PBBI) with subsequent behavioral, histopathological, and biomarker outcome assessments. There was a significant benefit on beam walk with the 5000 IU dose in CCI, but no benefit on any other motor task across models in OBTT. Also, no benefit of EPO treatment across the three TBI models was noted using the Morris water maze to assess cognitive deficits. Lesion volume analysis showed no treatment effects after either FPI or CCI; however, with the 5000 IU/kg dose of EPO, a paradoxical increase in lesion volume and percent hemispheric tissue loss was seen after PBBI. Biomarker assessments included measurements of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in blood at 4 or 24 h after injury. No treatment effects were seen on biomarker levels after FPI, whereas treatment at either dose exacerbated the increase in GFAP at 24 h in PBBI but attenuated 24-4 h delta UCH-L1 levels at high dose in CCI. Our data indicate a surprising lack of efficacy of EPO across three established TBI models in terms of behavioral, histopathological, and biomarker assessments. Although we cannot rule out the possibility that other doses or more prolonged treatment could show different effects, the lack of efficacy of EPO reduced enthusiasm for its further investigation in OBTT.
authors.affiliation: 1 Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami , Miami, Florida.|2 Bruce W. Carter Department of Veterans Affairs Medical Center , Miami, Florida.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bramlett
authors.affiliation: 1 Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami , Miami, Florida.
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
authors.affiliation: 3 Department of Neurological Surgery, Brain Trauma Research Center, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.affiliation: 4 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Shear
authors.affiliation: 4 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Kara E
authors.initials: KE
authors.lastname: Schmid
authors.affiliation: 5 Department of Neurosciences, University of Messina , Messina, Italy .
authors.forename: Stefania
authors.initials: S
authors.lastname: Mondello
authors.affiliation: 6 Center of Neuroproteomics and Biomarkers Research, Department of Psychiatry and Neuroscience, University of Florida. Gainesville, Florida.
authors.forename: Kevin K W
authors.initials: KK
authors.lastname: Wang
authors.affiliation: 7 Center for Innovative Research, Center for Neuroproteomics and Biomarkers Research , Banyan Biomarkers, Inc., Alachua, Florida.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hayes
authors.affiliation: 8 Department of Anatomy and Neurobiology, Virginia Commonwealth University , Richmond, Virginia.
authors.forename: John T
authors.initials: JT
authors.lastname: Povlishock
authors.affiliation: 4 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Tortella
authors.affiliation: 9 Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D000070642:Brain Injuries, Traumatic; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000097:blood; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D043222:Ubiquitin Thiolesterase / Q000097:blood
chemical_list: D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D004921:Erythropoietin; D043222:Ubiquitin Thiolesterase
keywords: biomarker; controlled cortical impact; fluid percussion; neuroprotection; penetrating ballistic-like brain injury; rat; therapy