SIMVASTATIN ATTENUATES MICROGLIAL CELLS AND ASTROCYTE ACTIVATION AND DECREASES INTERLEUKIN-1B LEVEL AFTER TRAUMATIC BRAIN INJURY

OBJECTIVE: Our previous studies demonstrated that simvastatin promotes neurological functional recovery after traumatic brain injury (TBI) in rat; however, the underlying mechanisms remain poorly understood. The purpose of this study was to investigate the anti-inflammatory effect of simvastatin by measuring the level of cytokines and activation of glial cells. METHODS: Controlled cortical impact injury was performed in adult male Wistar rats. The rats were randomly divided into 3 groups: sham, saline control group, and simvastatin treatment group. Simvastatin was administered orally starting at day 1 after TBI until animals were killed at days 1, 3, 7, 14, and 35 after treatment. Functional outcome was measured using modified neurological severity scores. Enzyme-linked immunosorbent assay and immunohistochemical staining were used to measure the expression of interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-a and to identify activated microglial cells and astrocytes. RESULTS: At days 1 and 3 after simvastatin or saline treatment, cytokine levels in the lesion boundary zone were significantly higher in the simvastatin- and saline-treated rats compared with the sham group, peaking at day 3. Simvastatin only reduced the level of IL-1 beta but not IL-6 and tumor necrosis factor-alpha, compared with the saline group. Also, simvastatin significantly reduced the number of activated microglial cells and astrocytes compared with the saline control animals. There was also a trend toward improvement of modified neurological severity score, reaching statistical significance (P = 0.003) toward the end of the trial. CONCLUSION: Our data demonstrate that TBI causes inflammatory reaction, including increased levels of IL-1 beta, IL-6, and tumor necrosis factor-alpha, as well as activated microglial cells. Simvastatin selectively reduces IL-1 beta expression and inhibits the activation of microglial cells and astrocytes after TBI, which might be one of the mechanisms underlying the therapeutic benefits of simvastatin treatment of TBI.