title: GW0742, a high-affinity PPAR-δ agonist, mediates protection in an organotypic model of spinal cord damage.
abstract: METHODS
  Experimental study of spinal cord injury (SCI) using an organotypic slice culture.
  
  
  OBJECTIVE
  To clarify the protective mechanism of PPAR-δ agonist GW0742 in the injured spinal cord using an in vitro model.
  
  
  BACKGROUND
  In vivo data suggest that ligands of the δ isoform have activity in a number of disease models that are partly driven by the inflammatory response. Moreover, reports from in vivo studies using models of ischemia reperfusion and Parkinson disease also have shown neuroprotection conferred by PPAR-δ. The biological role and function of PPAR-δ remains relatively unclear.
  
  
  METHODS
  Spinal cord from 6-week-old mice was cut into transverse slices of 400-μm thickness to generate the organotypic slice cultures. The slices were injured using a weight dropped onto the center of the slice. PPAR-δ agonist was applied at 10 μM at 1 hour before injury.
  
  
  RESULTS
  Our study shows that GW0742 incubation (10 μM) at 1 hour before transverse lesion significantly reduced (1) p38 mitogen-activated protein kinase (MAPK), (2) c-Jun N-terminal kinase (JNK/SAP kinase), (3) NF-κB activation, (4) loss of neurotrophic factors (BDNF, GDNF), (5) COX-2 expression, and (6) cell death.
  
  
  CONCLUSIONS
  GW0742 reduces the cellular and molecular changes occurring in SCI by targeting different downstream pathways modulating PPAR-δ receptors.
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Irene
authors.initials: I
authors.lastname: Paterniti
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meli
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D051379:Mice; D008954:Models, Biological; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009924:Organ Culture Techniques; D047494:PPAR delta / Q000819:agonists* / Q000502:physiology; D020033:Protein Isoforms / Q000819:agonists / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D018696:Neuroprotective Agents; D047494:PPAR delta; D020033:Protein Isoforms; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds