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

Abstract

BackgroundStatins 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).MethodsWith 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.ResultsResults 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.ConclusionsThis study indicates that PPAR-α can contribute to the anti-inflammatory activity of simvastatin in SCI.

Palmitoylethanolamide normalizes intestinal motility in a model of post‐inflammatory accelerated transit: involvement of CB1 receptors and TRPV1 channels

“…In the present study, we showed that GW6471 did not significantly counteract the effect of PEA on intestinal motility, although the effect of PEA was lost in GW6471-treated rats. The dose of GW6471 used in the present study has been previously shown to reveal PPARα-mediated anti-inflammatory effects of simvastatin (Esposito et al, 2012).…”

Men and women differ in their diurnal expression of monocyte peroxisome proliferator‐activated receptor‐α in the fed but not in the fasted state

“…In immune cells, PPARa primarily functions as an inhibitor of inflammatory pathways (4) and is found to be involved in the anti-inflammatory activity of cholesterollowering statin therapy (28). It is further hypothesized that PPARa in T cells may provide an explanation for the observation that women are being generally more susceptible to develop autoimmune diseases than men (29).…”

Hyperhomocysteinemia induces cardiac injury by up-regulation of p53-dependent Noxa and Bax expression through the p53 DNA methylation in ApoE<sup>−/−</sup> mice

“…Bound antibodies were viewed under an Olympus BX51 microscope. Immunocytochemistry photographs were assessed by densitometry as described previously [14] and analyzed using Image Pro-Plus 6.0 software (Media Cybernetics Company, Silver Spring, USA). The total OD value and area of intracellular brown staining for each section were measured.…”