Simvastatin reduces secondary brain injury caused by cortical contusion in rats: Possible involvement of TLR4/NF-κB pathway

Document Type

Article

Abstract

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-κB) 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-κB and the downstream inflammatory agents, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), 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-κB-mediated inflammatory response in the injured rat brain, and this may be one mechanism by which simvastatin improves outcome following TBI. © 2009 Elsevier Inc. All rights reserved.

Keywords

Cerebral inflammation, Nuclear factor-kappa B, Simvastatin, Toll-like receptor 4, Traumatic brain injury

Publication Date

4-1-2009

Publication Title

Experimental Neurology

ISSN

00144886

E-ISSN

10902430

Volume

216

Issue

2

First Page

398

Last Page

406

PubMed ID

19166837

Digital Object Identifier (DOI)

10.1016/j.expneurol.2008.12.019

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