Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: Involvement of PPAR-α

Background: statins such as simvastatin are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) reductase used in the prevention of cardiovascular disease. in addition to their cholesterol-lowering activities,statins exert pleiotropic anti-inflammatory effects,which might contribute to their beneficial effects on lipid-unrelated inflammatory diseases. recently it has been demonstrated that the peroxisome proliferator-activated receptor (ppar)-α mediates anti-inflammatory effects of simvastatin in vivo models of acute inflammation. moreover,previous results suggest that ppar-α plays a role in control of secondary inflammatory process associated with spinal cord injury (sci).methods: with the aim to characterize the role of ppar-α in simvastatin activity,we tested the efficacy of simvastatin (10 mg/kg dissolved in saline i.p. 1 h and 6 h after the trauma) in an experimental model of sci induced in mice by extradural compression of the spinal cord (t6-t7 level) using an aneurysm clip with a closing force of 24 g via a four-level t5-t8 laminectomy,and comparing mice lacking ppar-α (ppar-α ko) with wild type (wt) mice. in order to elucidate whether the effects of simvastatin are due to activation of the ppar-α,we also investigated the effect of a ppar-α antagonist,gw6471 (1 mg/kg administered i.p. 30 min prior treatment with simvastatin) on the protective effects of on simvastatin.results: results indicate that simvastatin activity is weakened in ppar-α ko mice,as compared to wt controls. in particular,simvastatin was less effective in ppar-α ko,compared to wt mice,as evaluated by inhibition of the degree of spinal cord inflammation,neutrophil infiltration,nitrotyrosine formation,pro-inflammmatory cytokine expression,nuclear factor (nf)-κb activation,inducible nitric-oxide synthase (inos) expression,and apoptosis. in addition we demonstrated that gw6471 significantly antagonized the effect of the statin and thus abolished the protective effect.conclusions: this study indicates that ppar-α can contribute to the anti-inflammatory activity of simvastatin in sci. © 2012 esposito et al; licensee biomed central ltd.