Simvastatin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy

Andrea Mountney, Helen M. Bramlett, C. Edward Dixon, Stefania Mondello, W. Dalton Dietrich, Kevin K.W. Wang, Krista Caudle, Philip E. Empey, Samuel M. Poloyac, Ronald L. Hayes, John T. Povlishock, Frank C. Tortella, Patrick M. Kochanek, Deborah A. Shear

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)567-580
Number of pages14
JournalJournal of neurotrauma
Volume33
Issue number6
DOIs
StatePublished - Mar 15 2016

Keywords

  • biomarker
  • controlled cortical impact
  • fluid percussion
  • micropig
  • neuroprotection
  • penetrating ballistic-like brain injury
  • rat
  • statin
  • therapy

ASJC Scopus subject areas

  • Clinical Neurology

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    Mountney, A., Bramlett, H. M., Dixon, C. E., Mondello, S., Dietrich, W. D., Wang, K. K. W., Caudle, K., Empey, P. E., Poloyac, S. M., Hayes, R. L., Povlishock, J. T., Tortella, F. C., Kochanek, P. M., & Shear, D. A. (2016). Simvastatin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy. Journal of neurotrauma, 33(6), 567-580. https://doi.org/10.1089/neu.2015.4130