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

Abstract

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.

• Authors: Emanuela Esposito, Barbara Rinaldi, Emanuela Mazzon, Maria Donniacuo, Daniela Impellizzeri, Irene Paterniti, Annalisa Capuano, Placido Bramanti, Salvatore Cuzzocrea
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 9 Pg. 81 (Apr 26 2012) ISSN: 1742-2094 [Electronic] England
• PMID: 22537532 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• PPAR alpha
• Simvastatin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Disease Models, Animal
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• PPAR alpha (deficiency)
• Random Allocation
• Simvastatin (therapeutic use)
• Spinal Cord Injuries (drug therapy, metabolism)
• Thoracic Vertebrae