Cyclosporine Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy
| Autor: | Kevin K.W. Wang, W. Dalton Dietrich, Hong Q. Yan, John T. Povlishock, Patrick M. Kochanek, Philip E. Empey, Ying Deng-Bryant, C. Edward Dixon, Helen M. Bramlett, Ronald L. Hayes, Stefania Mondello, Frank C. Tortella, Deborah A. Shear |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Traumatic brain injury Morris water navigation task Neuroprotection phosphatase Rats Sprague-Dawley Random Allocation 03 medical and health sciences 0302 clinical medicine Therapeutic index Brain Injuries Traumatic Glial Fibrillary Acidic Protein medicine Animals rat calcineurin therapy Glial fibrillary acidic protein biology fluid percussion business.industry Recovery of Function medicine.disease Rats Surgery Calcineurin Disease Models Animal 030104 developmental biology Anesthesia Toxicity biomarker calcineurin controlled cortical impact fluid percussion neuroprotection penetrating ballistic-like brain injury phosphatase rat therapy Neurology (clinical) Cyclosporine biology.protein biomarker Biomarker (medicine) neuroprotection Neurology (clinical) penetrating ballistic-like brain injury controlled cortical impact business Ubiquitin Thiolesterase Biomarkers Immunosuppressive Agents 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neurotrauma. 33:553-566 |
| ISSN: | 1557-9042 0897-7151 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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