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.