title: Cyclosporine Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.
abstract: Operation Brain Trauma Therapy (OBTT) is a consortium of investigators using multiple pre-clinical models of traumatic brain injury (TBI) to bring acute therapies to clinical trials. To screen therapies, we used three rat models (parasagittal fluid percussion injury [FPI], controlled cortical impact [CCI], and penetrating ballistic-like brain injury [PBBI]). We report results of the third therapy (cyclosporin-A; cyclosporine; [CsA]) tested by OBTT. At each site, rats were randomized to treatment with an identical regimen (TBI + vehicle, TBI + CsA [10 mg/kg], or TBI + CsA [20 mg/kg] given intravenously at 15 min and 24 h after injury, and sham). We assessed motor and Morris water maze (MWM) tasks over 3 weeks after TBI and lesion volume and hemispheric tissue loss at 21 days. In FPI, CsA (10 mg/kg) produced histological protection, but 20 mg/kg worsened working memory. In CCI, CsA (20 mg/kg) impaired MWM performance; surprisingly, neither dose showed benefit on any outcome. After PBBI, neither dose produced benefit on any outcome, and mortality was increased (20 mg/kg) partly caused by the solvent vehicle. In OBTT, CsA produced complex effects with histological protection at the lowest dose in the least severe model (FPI), but only deleterious effects as model severity increased (CCI and 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 positive treatment effects were seen on biomarker levels in any of the models, whereas significant increases in 24 h UCH-L1 levels were seen with CsA (20 mg/kg) after CCI and 24 h GFAP levels in both CsA treated groups in the PBBI model. Lack of behavioral protection in any model, indicators of toxicity, and a narrow therapeutic index reduce enthusiasm for clinical translation.
authors.affiliation: 1 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: 2 Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami , Miami, Florida.|3 Bruce W. Carter Department of Veterans Affairs Medical Center , Miami, Florida.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bramlett
authors.affiliation: 2 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: 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: 1 Department of Neurological Surgery, Brain Trauma Research Center, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: Hong Q
authors.initials: HQ
authors.lastname: Yan
authors.affiliation: 4 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Deng-Bryant
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 Center for Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy , Pittsburgh, Pennsylvania.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Empey
authors.affiliation: 9 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: 10 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; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000097:blood; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D011897:Random Allocation; 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; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D043222:Ubiquitin Thiolesterase
keywords: biomarker; calcineurin; controlled cortical impact; fluid percussion; neuroprotection; penetrating ballistic-like brain injury; phosphatase; rat; therapy