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.