Evidence for the role of peroxisome proliferator-activated receptor-beta/delta in the development of spinal cord injury.
Several lines of evidence suggest a biological role for peroxisome proliferator-activated receptor (PPAR)-beta/delta in the pathogenesis many diseases. The aim of the present study was to evaluate the contribution of PPAR-beta/delta in the secondary damage in experimental spinal cord injury (SCI) in mice. To this purpose, we used 4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid (GW0742), a high-affinity PPAR-beta/delta agonist. Spinal cord trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5 to T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of inflammatory mediators, tissue damage, and apoptosis. GW0742 treatment (0.3 mg kg(-1) i.p.) 1 and 6 h after the SCI significantly reduced 1) the degree of spinal cord inflammation and tissue injury (histological score), 2) neutrophil infiltration (myeloperoxidase activity), 3) nitrotyrosine formation, 4) proinflammatory cytokines expression, 5) nuclear factor-kappaB activation, 6) inducible nitric-oxide synthase expression, and 6) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, FasL, Bax, and Bcl-2 expression). Moreover, GW0742 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). To elucidate whether the protective effects of GW0742 are related to activation of the PPAR-beta/delta receptor, we also investigated the effect of PPAR-beta/delta antagonist methyl 3-({[2-(methoxy)-4 phenyl]amino}sulfonyl)-2-thiophenecarboxylate (GSK0660) on the protective effects of GW0742. GSK0660 (1 mg/kg i.p. 30 min before treatment with GW0742) significantly blocked the effect of the PPAR-beta/delta agonist and thus abolished the protective effect. Our results clearly demonstrate that GW0742 treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.
Paterniti
Irene
I
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.
Esposito
Emanuela
E
Mazzon
Emanuela
E
Galuppo
Maria
M
Di Paola
Rosanna
R
Bramanti
Placido
P
Kapoor
Amar
A
Thiemermann
Christoph
C
Cuzzocrea
Salvatore
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D053222:Fas Ligand Protein / Q000378:metabolism; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D048068:PPAR-beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism / Q000502:physiology; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000503:physiopathology*; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D010636:Phenols; D013438:Sulfhydryl Compounds
D016207:Cytokines; D053222:Fas Ligand Protein; D019001:Nitric Oxide Synthase; D047494:PPAR delta; D048068:PPAR-beta; D009195:Peroxidase; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; C529769:GSK0660; C002744:3-nitrotyrosine; 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