Journal of neurotrauma
-
Journal of neurotrauma · Mar 2016
Simvastatin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.
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. ⋯ 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.
-
Journal of neurotrauma · Mar 2016
Insight into Preclinical Models of Traumatic Brain Injury Using Circulating Brain Damage Biomarkers: Operation Brain Trauma Therapy.
Operation Brain Trauma Therapy (OBTT) is a multicenter pre-clinical drug screening consortium testing promising therapies for traumatic brain injury (TBI) in three well-established models of TBI in rats--namely, parasagittal fluid percussion injury (FPI), controlled cortical impact (CCI), and penetrating ballistic-like brain injury (PBBI). This article presents unique characterization of these models using histological and behavioral outcomes and novel candidate biomarkers from the first three treatment trials of OBTT. Adult rats underwent CCI, FPI, or PBBI and were treated with vehicle (VEH). ⋯ Significant differences were also found comparing shams across the models. Our findings (1) demonstrate that TBI models display specific biomarker profiles, functional deficits, and pathological consequence; (2) support the concept that there are different cellular, molecular, and pathophysiological responses to TBI in each model; and (3) advance our understanding of TBI, providing opportunities for a successful translation and holding promise for theranostic applications. Based on our findings, additional studies in pre-clinical models should pursue assessment of GFAP as a surrogate histological and/or theranostic end-point.
-
Journal of neurotrauma · Mar 2016
ReviewSynthesis of Findings, Current Investigations, and Future Directions: Operation Brain Trauma Therapy.
Operation Brain Trauma Therapy (OBTT) is a fully operational, rigorous, and productive multicenter, pre-clinical drug and circulating biomarker screening consortium for the field of traumatic brain injury (TBI). In this article, we synthesize the findings from the first five therapies tested by OBTT and discuss both the current work that is ongoing and potential future directions. Based on the results generated from the first five therapies tested within the exacting approach used by OBTT, four (nicotinamide, erythropoietin, cyclosporine A, and simvastatin) performed below or well below what was expected based on the published literature. ⋯ The sixth and seventh therapies have just completed testing (glibenclamide and Kollidon VA 64), and an eighth drug (AER 271) is in testing. Incorporation of circulating brain injury biomarker assessments into these pre-clinical studies suggests considerable potential for diagnostic and theranostic utility of glial fibrillary acidic protein in pre-clinical studies. Given the failures in clinical translation of therapies in TBI, rigorous multicenter, pre-clinical approaches to therapeutic screening such as OBTT may be important for the ultimate translation of therapies to the human condition.
-
Journal of neurotrauma · Mar 2016
Review Meta AnalysisMethylprednisolone for the treatment of patients with acute spinal cord injuries: A systematic review and meta-analysis.
Previous meta-analyses of methylprednisolone (MPS) for patients with acute traumatic spinal cord injuries (TSCIs) have not addressed confidence in the quality of evidence used for pooled effect estimates, and new primary studies have been recently published. We aimed to determine whether MPS improves motor recovery and is associated with increased risks for adverse events. We searched MEDLINE, EMBASE, and The Cochrane Library, and two reviewers independently screened articles, extracted data, and evaluated risk of bias. ⋯ Observational studies demonstrated a significantly increased risk for gastrointestinal bleeding (nine studies: 2857 participants; RR, 2.18; 95% CI, 1.13-4.19; p = 0.02, very low confidence), but RCTs did not. Pooled evidence does not demonstrate a significant long-term benefit for MPS in patients with acute TSCIs and suggests it may be associated with increased gastrointestinal bleeding. These findings support current guidelines against routine use, but strong recommendations are not warranted because confidence in the effect estimates is limited.