title: Molecular evidence for the involvement of PPAR-δ and PPAR-γ in anti-inflammatory and neuroprotective activities of palmitoylethanolamide after spinal cord trauma.
abstract: BACKGROUND
  Palmitoylethanolamide (PEA) is an endogenous fatty acid amide displaying anti-inflammatory and analgesic actions. Moreover, several data have suggested that PEA reduced inflammation and tissue injury associated with spinal cord trauma and showed a regulatory role for peroxisome proliferator-activated receptor (PPAR)-α signaling in the neuroprotective effect of PEA. However, several other mechanisms could explain the anti-inflammatory and anti-hyperalgesic effects of PEA, including the activation of PPAR-δ and PPAR-γ. The aim of the present study was to carefully investigate the exact contribution of PPAR-δ and PPAR-γ in addition to PPAR-α, in the protective effect of PEA on secondary inflammatory damage associated with an experimental model of spinal cord injury (SCI).
  
  
  METHODS
  SCI was induced in mice through a spinal cord compression by the application of vascular clips (force of 24 g) to the dura via a four-level T5 to T8 laminectomy, and PEA (10 mg/kg, intraperitoneally, 1 and 6 hours after SCI) was injected into wildtype mice and into mice lacking PPAR-α (PPAR-αKO). To deepen the ability of specific PPAR-δ and PPAR-γ antagonists to reverse the effect of PEA, mice were administered GSK0660 or GW9662, 30 minutes before PEA injection.
  
  
  RESULTS
  Genetic ablation of PPAR-α in mice exacerbated spinal cord damage, while PEA-induced neuroprotection seemed be abolished in PPARαKO mice. Twenty-four hours after spinal cord damage, immunohistological and biochemical studies were performed on spinal cord tissue. Our results indicate that PPAR-δ and PPAR-γ also mediated the protection induced by PEA. In particular, PEA was less effective in PPAR-αKO, GSK0660-treated or GW9662-pretreated mice, as evaluated by the degree of spinal cord inflammation and tissue injury, neutrophil infiltration, proinflammmatory cytokine, inducible nitric oxide synthase expression and motor function. PEA is also able to restore PPAR-δ and PPAR-γ expression in spinal cord tissue.
  
  
  CONCLUSIONS
  This study indicates that PPAR-δ and PPAR-γ can also contribute to the anti-inflammatory activity of PEA in SCI.
authors: Department of Biological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, Messina 31-98166, Italy.
authors: Irene
authors: I
authors: Paterniti
authors: Daniela
authors: D
authors: Impellizzeri
authors: Rosalia
authors: R
authors: Crupi
authors: Rossana
authors: R
authors: Morabito
authors: Michela
authors: M
authors: Campolo
authors: Emanuela
authors: E
authors: Esposito
authors: Salvatore
authors: S
authors: Cuzzocrea
mesh_terms: D000577:Amides; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000627:therapeutic use*; D063388:Endocannabinoids / Q000378:metabolism / Q000627:therapeutic use*; D004983:Ethanolamines / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D047494:PPAR delta / Q000172:deficiency* / Q000235:genetics; D047495:PPAR gamma / Q000172:deficiency* / Q000235:genetics; D010169:Palmitic Acids / Q000378:metabolism / Q000627:therapeutic use*; D011897:Random Allocation; D013119:Spinal Cord Injuries / Q000235:genetics / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D063388:Endocannabinoids; D004983:Ethanolamines; D018696:Neuroprotective Agents; D047494:PPAR delta; D047495:PPAR gamma; D010169:Palmitic Acids; C005958:palmidrol
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