Effect of Cyclopentanone Prostaglandin 15-deoxy-$pgj2 on Early Functional Recovery from Experimental Spinal Cord Injury

Peroxisome proliferatorYactivated receptor (PPAR) + is a member of the nuclear-receptor superfamily that binds to DNA with retinoid X receptors as PPARYretinoid X receptor heterodimers. Recent evidence also suggests that the cyclopentenone prostaglandin 15-deoxy-$PGJ2 (15d-PGJ2), which is a metabolite of the prostaglandin D2, functions as an endogenous ligand for PPAR-+ We postulated that 15d-PGJ2 would attenuate inflammation, investigating the effects on the degree of experimental spinal cord trauma induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Furthermore, 15d-PGJ2 reduced (1) spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) nuclear factorY.B activation, (4) expression of iNOS, nitrotyrosine and TNF-!, and (5) apoptosis (terminal deoxynucleotidyltransferase-mediated uridine triphosphate end labeling staining, Bax, Bcl-2, and FAS-L expression). In a separate set of experiments, 15d-PGJ2 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). To elucidate whether the protective effects of 15d-PGJ2 are related to activation of the PPAR-+ receptor, we also investigated the effect of a PPAR-+ antagonist, GW 9662, on the protective effects of 15d-PGJ2. GW9662 (1 mg/kg administered i.p. 30 min before treatment with 15d-PGJ2) significantly antagonized the effect of the PPAR-+ agonist and, thus, abolished the protective effect. Taken together, our results clearly demonstrate that treatment with 15d-PGJ2 reduces the development of inflammation and tissue injury associated with spinal cord trauma. KEYWORDS—PPAR-+ spinal cord injury, inflammation, apoptosis