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)-alpha mediates anti-inflammatory effects of simvastatin in vivo models of acute inflammation. Moreover, previous results suggest that PPAR-alpha 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-alpha 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-alpha (PPAR-alpha KO) with wild type (WT) mice. In order to elucidate whether the effects of simvastatin are due to activation of the PPAR-alpha, we also investigated the effect of a PPAR-alpha 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-alpha KO mice, as compared to WT controls. In particular, simvastatin was less effective in PPAR-alpha 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)-kappa B 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-alpha can contribute to the anti-inflammatory activity of simvastatin in SCI.