Abstract
Several lines of evidence suggest a biological role for peroxisome proliferator-activated receptor (PPAR)-β/δ in the pathogenesis many diseases. The aim of the present study was to evaluate the contribution of PPAR-β/δ 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-β/δ 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-κB 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-β/δ receptor, we also investigated the effect of PPAR-β/δ 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-β/δ 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.
Footnotes
This study was supported by Minister of University [Grant PRIN 2007]. C.T. is a Senior Fellow of the British Heart Foundation [Grant FS 96/018].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.165605.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- SCI
- spinal cord injury
- PPAR
- peroxisome proliferator-activated receptor
- GW0742
- 4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid
- GSK0660
- methyl 3-({[2-(methoxy)-4 phenyl]amino}sulfonyl)-2-thiophenecarboxylate
- MPO
- myeloperoxidase
- TNF
- tumor necrosis factor
- iNOS
- inducible nitric-oxide synthase
- PBS
- phosphate-buffered saline
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- NF-κB
- nuclear factor-κB
- PMSF
- phenylmethylsulfonyl fluoride
- MDA
- malondialdehyde
- BBB
- Basso, Beattie, and Bresnahan
- IL
- interleukin
- LPS
- lipopolysaccharide.
- Received January 6, 2010.
- Accepted February 19, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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