Simvastatin reduces secondary brain injury caused by cortical contusion in rats: possible involvement of TLR4/NF-kappaB pathway.
Simvastatin, a cholesterol-lowering agent, has demonstrated neuroprotective effects against brain injury, but the underlying mechanisms remain unclear. This study was undertaken to evaluate the effect of simvastatin on the Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-kappaB) related signaling pathway and secondary brain injury in rats after traumatic brain injury (TBI). Adult male Wistar rats were divided into four groups: (1) Sham group (n=25); (2) Sham+vehicle group (n=25); (3) TBI+vehicle group (n=30); and (4) TBI+simvastatin group (n=30). Right parietal cortical contusion was made by using a weight-dropping method. In TBI+simvastatin group, simvastatin was administered orally at a dose of 37.5 mg/kg at 1 and 6 h after TBI. Brain samples were extracted at 24 h after trauma. As a result, we found that treatment with simvastatin markedly inhibited the mRNA and protein expressions of TLR4, NF-kappaB and the downstream inflammatory agents, such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and intercellular adhesion molecule-1 (ICAM-1). Administration of simvastatin following TBI significantly ameliorated the secondary brain damage, such as cortical apoptosis, brain edema, blood-brain barrier (BBB) impairment, and motor deficits. In conclusion, post-TBI simvastatin administration may attenuate TLR4/NF-kappaB-mediated inflammatory response in the injured rat brain, and this may be one mechanism by which simvastatin improves outcome following TBI.
Chen
Gang
G
Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China. Dr.Chen@utoronto.ca
Zhang
Shiming
S
Shi
Jixin
J
Ai
Jinglu
J
Qi
Meng
M
Hang
Chunhua
C
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D001930:Brain Injuries / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling / Q000379:methods; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009069:Movement Disorders / Q000209:etiology / Q000517:prevention & control; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000627:therapeutic use*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D018799:Intercellular Adhesion Molecule-1; D019821:Simvastatin