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 role 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 spinal cord trauma. Previous results suggest that peroxisome proliferator-activated receptor alpha (PPAR-alpha), a nuclear receptor protein that functions as a transcription factor activated by fatty acids, plays a role in control of secondary inflammatory process associated with spinal cord injury (SCI). With the aim to characterize the role of PPAR-alpha in melatonin-mediated anti-inflammatory activity, we tested the efficacy of melatonin (30 mg/kg) in an experimental model of spinal cord trauma, induced in mice, by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy, and comparing mice lacking PPAR-alpha (PPAR-alpha KO) with wild-type (WT) mice. The results obtained indicate that melatonin-mediated antiinflammatory activity is weakened in PPAR-alpha KO mice, as compared to WT controls. In particular, melatonin was less effective in PPAR-alpha KO, compared to WT mice, as evaluated by inhibition of the degree of spinal cord inflammation and tissue injury, neutrophil infiltration, pro-inflammatory cytokine expression, nuclear factor kappa B (NF-kappa B) activation, and inducible nitric oxide synthase (iNOS) expression. This study indicates that PPAR-alpha can contribute to the anti-inflammatory activity of melatonin in SCI.