title: Simvastatin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.
abstract: 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.
authors.affiliation: 1 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mountney
authors.affiliation: 2 Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami , Miami, Florida; Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bramlett
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 Department of Neurosciences, University of Messina , Messina, Italy .
authors.forename: Stefania
authors.initials: S
authors.lastname: Mondello
authors.affiliation: 2 Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami , Miami, Florida; Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida.
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
authors.affiliation: 5 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: 1 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Krista
authors.initials: K
authors.lastname: Caudle
authors.affiliation: 6 University of Pittsburgh School of Pharmacy , Pittsburgh, Pennsylvania.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Empey
authors.affiliation: 6 University of Pittsburgh School of Pharmacy , Pittsburgh, Pennsylvania.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Poloyac
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: 1 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
authors.affiliation: 1 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
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D000070642:Brain Injuries, Traumatic; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000097:blood; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase / Q000097:blood
chemical_list: D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D019821:Simvastatin; D043222:Ubiquitin Thiolesterase
keywords: biomarker; controlled cortical impact; fluid percussion; micropig; neuroprotection; penetrating ballistic-like brain injury; rat; statin; therapy