Simvastatin attenuates microglial cells and astrocyte activation and decreases interleukin-1beta 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)-1beta, IL-6, and tumor necrosis factor-alpha 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-1beta 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.


CONCLUSIONS
Our data demonstrate that TBI causes inflammatory reaction, including increased levels of IL-1beta, IL-6, and tumor necrosis factor-alpha, as well as activated microglial cells. Simvastatin selectively reduces IL-1beta 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.
Li
Bo
B
Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA.
Mahmood
Asim
A
Lu
Dunyue
D
Wu
Hongtao
H
Xiong
Ye
Y
Qu
Changsheng
C
Chopp
Michael
M
D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects*; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005904:Glial Fibrillary Acidic Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D019821:Simvastatin; C067980:CD68 antigen, human; D000097382:CD68 Molecule