PPAR-α Modulates the Anti-Inflammatory Effect of Melatonin in the Secondary Events of Spinal Cord Injury

Melatonin is the principal secretory product of the pineal gland, and its rote as an immunomodulator is well established. Recent evidence shows that melatonin is a scavenger of oxyradicals and peroxynitrite and reduces the development of inflammation and tissue injury events associated with spinai cord trauma. Previous results suggest that peroxisome proliferator-activated receptor cx (PPAR-cx.), a nuclear receptor protein that functions as a transcription factor activated by fatty acids, plays a rote in control of secondary intlammatory process associated with spinai cord injury (SCI). With the aim to characterize the rote of PPAR-cx. in melatonin-mediated anti-inflammatory activity, we tested the efficacy ofmelatonin (30 mg/kg) in an experimental model of spinai cord trauma, induced in mice, by the application of vascular clips (force of24 g) to the dura via a four-level T5- T8 laminectomy, and comparing mice lacking PPAR-cx. (PPAR-cx. KO) with wild-type (WT) mice. The results obtained indicate that melatonin-mediated antiinflammatory activity is weakened in PPAR-cx. KO mice, as compared to WT controls. In particular, melatonin was less effective in PPAR-cx. KO, compared to WT mice, as evaluated by inhibition of the degree of spinai cord intlammation and tissue injury, neutrophil infiltration, pro-intlammatory cytokine expression, nuclear factor KB (NF-KB) activation, and inducible nitric oxide synthase (iNOS) expression. This study indicates that PPAR-cx. can contribute to the anti-intlammatory activity of melatonin in SCI.