GW0742, a High-Affinity PPAR-δ Agonist, Mediates Protection in an Organotypic Model of Spinal Cord Damage

Study Design. Experimental study of spinal cord injury (SCI) using an organotypic slice culture. Objective. To clarify the protective mechanism of PPAR-delta agonist GW0742 in the injured spinal cord using an in vitro model. Summary of Background Data. In vivo data suggest that ligands of the delta 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-delta. The biological role and function of PPAR-delta remains relatively unclear. Methods. Spinal cord from 6-week-old mice was cut into transverse slices of 400-mu m thickness to generate the organotypic slice cultures. The slices were injured using a weight dropped onto the center of the slice. PPAR-delta agonist was applied at 10 mu M at 1 hour before injury. Results. Our study shows that GW0742 incubation (10 mu M) 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-kappa B activation, (4) loss of neurotrophic factors (BDNF, GDNF), (5) COX-2 expression, and (6) cell death. Conclusion. GW0742 reduces the cellular and molecular changes occurring in SCI by targeting different downstream pathways modulating PPAR-delta receptors.