Simvastatin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy
| Autor: | W. Dalton Dietrich, Frank C. Tortella, Kevin K.W. Wang, Patrick M. Kochanek, Helen M. Bramlett, Stefania Mondello, Andrea Mountney, John T. Povlishock, Krista Caudle, Philip E. Empey, C. Edward Dixon, Ronald L. Hayes, Deborah A. Shear, Samuel M. Poloyac |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Simvastatin biomarker controlled cortical impact fluid percussion micropig neuroprotection penetrating ballistic-like brain injury rat statin therapy Neurology (clinical) Statin medicine.drug_class Traumatic brain injury Morris water navigation task Neuroprotection Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Oral administration Brain Injuries Traumatic Glial Fibrillary Acidic Protein medicine Animals rat therapy Glial fibrillary acidic protein biology business.industry fluid percussion statin Recovery of Function medicine.disease Rats Disease Models Animal 030104 developmental biology Neuroprotective Agents Anesthesia biology.protein Biomarker (medicine) biomarker neuroprotection micropig Neurology (clinical) Hydroxymethylglutaryl-CoA Reductase Inhibitors penetrating ballistic-like brain injury business controlled cortical impact Ubiquitin Thiolesterase 030217 neurology & neurosurgery Biomarkers medicine.drug |
| Popis: | Simvastatin, the fourth drug selected for testing by Operation Brain Trauma Therapy (OBTT), is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor used clinically to reduce serum cholesterol. In addition, simvastatin has demonstrated potent antineuroinflammatory and brain edema reducing effects and has shown promise in promoting functional recovery in pre-clinical models of traumatic brain injury (TBI). The purpose of this study was to assess the potential neuroprotective effects of oral administration of simvastatin on neurobehavioral, biomarker, and histopathological outcome measures compared across three pre-clinical TBI animal models. Adult male Sprague-Dawley rats were exposed to either moderate fluid percussion injury (FPI), controlled cortical impact injury (CCI), or penetrating ballistic-like brain injury (PBBI). Simvastatin (1 or 5 mg/kg) was delivered via oral gavage at 3 h post-injury and continued once daily out to 14 days post-injury. Results indicated an intermediate beneficial effect of simvastatin on motor performance on the gridwalk (FPI), balance beam (CCI), and rotarod tasks (PBBI). No significant therapeutic benefit was detected, however, on cognitive outcome across the OBTT TBI models. In fact, Morris water maze (MWM) performance was actually worsened by treatment in the FPI model and scored full negative points for low dose in the MWM latency and swim distance to locate the hidden platform. A detrimental effect on cortical tissue loss was also seen in the FPI model, and there were no benefits on histology across the other models. Simvastatin also produced negative effects on circulating glial fibrillary acidic protein biomarker outcomes that were evident in the FPI and PBBI models. Overall, the current findings do not support the beneficial effects of simvastatin administration over 2 weeks post-TBI using the oral route of administration and, as such, it will not be further pursued by OBTT. |
| Databáze: | OpenAIRE |
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