ABSTRACT
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 α (PPAR-α), 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-α 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-α (PPAR-α KO) with wild-type (WT) mice.The results obtained indicate that melatonin-mediated anti-inflammatory activity is weakened in PPAR-α KO mice, as compared to WT controls. In particular, melatonin was less effective in PPAR-α 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 κB (NF-κB) activation, and inducible nitric oxide synthase (iNOS) expression. This study indicates that PPAR-α can contribute to the anti-inflammatory activity of melatonin in SCI.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Inflammation/drug therapy , Melatonin/pharmacology , PPAR alpha/metabolism , Spinal Cord Injuries/metabolism , Animals , Apoptosis/drug effects , Disease Models, Animal , Mice, Knockout , NF-kappa B/metabolism , Neutrophil Infiltration/drug effects , Nitric Oxide Synthase Type II/metabolism , PPAR alpha/genetics , Spinal Cord Injuries/drug therapy , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Palmitoylethanolamide (PEA), a special food for medical purposes, has anti-inflammatory and neuroprotective effects. Nevertheless, PEA lacks direct ability to prevent free radical formation. Polydatin (PLD), a natural precursor of resveratrol, has antioxidant activity. The combination of PEA and PLD could have beneficial effects on oxidative stress induced by inflammatory processes. In the present study, we compared the effects of micronized PEA (PEA-m) and PLD association (PEA-m+PLD) with a new co-micronized composite containing PEA and PLD (m(PEA/PLD)) in the rat paw model of carrageenan (CAR)-induced acute inflammation. Intraplantar injection of CAR led to a time-dependent development of peripheral inflammation, in terms of paw edema, cytokine release in paw exudates, nitrotyrosine formation, inducible nitric oxide synthase and cyclooxygenase-2 expression. m(PEA/PLD) reduced all measured parameters. Thermal hyperalgesia and mechanical allodynia were also markedly reduced. At the spinal cord level, manganese superoxide dismutase (MnSOD) was found to be nitrated and subsequently deactivated. Further, m(PEA/PLD) treatment increased spinal MnSOD expression, prevented IkB-α degradation and nuclear factor-κB translocation, suggesting a possible role on central sensitization. m(PEA/PLD) showed more robust anti-inflammatory and anti-hyperalgesic effects compared to the simple association of PEA-m and PLD. This composite formulation approach opens a new therapeutic strategy for the development of novel non-narcotic anti-hyperalgesic agents.
Subject(s)
Carrageenan/pharmacology , Edema/chemically induced , Edema/drug therapy , Ethanolamines/chemistry , Ethanolamines/pharmacology , Glucosides/chemistry , Glucosides/pharmacology , Palmitic Acids/chemistry , Palmitic Acids/pharmacology , Stilbenes/chemistry , Stilbenes/pharmacology , Active Transport, Cell Nucleus/drug effects , Administration, Oral , Amides , Animals , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cyclooxygenase 2/metabolism , Cytokines/metabolism , Disease Models, Animal , Drug Compounding , Drug Interactions , Edema/immunology , Edema/metabolism , Ethanolamines/administration & dosage , Ethanolamines/therapeutic use , Gene Expression Regulation, Enzymologic/drug effects , Glucosides/administration & dosage , Glucosides/therapeutic use , Hyperalgesia/drug therapy , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/immunology , Inflammation/metabolism , Male , NF-KappaB Inhibitor alpha/metabolism , Neutrophil Infiltration/drug effects , Nitric Oxide Synthase Type II/metabolism , Palmitic Acids/administration & dosage , Palmitic Acids/therapeutic use , Proteolysis/drug effects , Rats , Rats, Sprague-Dawley , Stilbenes/administration & dosage , Stilbenes/therapeutic use , Superoxide Dismutase/metabolism , Transcription Factor RelA/metabolism , Tyrosine/analogs & derivatives , Tyrosine/biosynthesisABSTRACT
Contrast-induced nephropathy (CIN) is a complication in patients after administration of iodinated contrast media. Several risk factors contribute to the development and progression of CIN, including hypertension, diabetes, and dyslipidemia. Animal models of CIN by surgical intervention to reproduce its clinical and pathology has been developed, and thus, therapeutic methods tested. Palmitoylethanolamide (PEA) is a member of the fatty acid ethanolamine family with analgesic and anti-inflammatory effects. In this study, we analyzed streptozotocin-induced diabetes model and in an another set of experiment a surgical remotion of the kidney with the aim of evaluating effect of ultramicronized Palmitoylethanolamide (PEA-um(®)) on contrast induced renal disfunction and glomerular morphology alteration. In a first step of our study, we demonstrated that PEA-um(®) significantly reduced CIN-mediated glomerular dysfunction, modulates Na(+) and K(+) levels in plasma and decreased urine and plasma NGAL levels and α-GST urine levels. Moreover, in a second set of experiment we investigated how PEA-um(®) reduced creatinine and BUN plasma levels after nephrectomy, ameliorate renal and medullary blood flow and re-established renal parenchymal after CIN induction as well as after nephrectomy. Take together our results demonstrated that PEA-um(®) are able to preventing CIN in diabetic rats and alteration of biochemical parameters after nephrectomy.
