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

Esposito, Emanuela, PhD*; Paterniti, Irene, MS*; Meli, Rosaria, PhD; Bramanti, Placido, MD; Cuzzocrea, Salvatore, PhD*,‡

doi: 10.1097/BRS.0b013e3182276d88
Basic Science
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Study Design. Experimental study of spinal cord injury (SCI) using an organotypic slice culture.

Objective. To clarify the protective mechanism of PPAR-δ agonist GW0742 in the injured spinal cord using an in vitro model.

Summary of Background Data. In vivo data suggest that ligands of the δ 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-δ. The biological role and function of PPAR-δ remains relatively unclear.

Methods. Spinal cord from 6-week-old mice was cut into transverse slices of 400-μm thickness to generate the organotypic slice cultures. The slices were injured using a weight dropped onto the center of the slice. PPAR-δ agonist was applied at 10 μM at 1 hour before injury.

Results. Our study shows that GW0742 incubation (10 μM) 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-κB 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-δ receptors.

To clarify the protective mechanism of PPAR-δ agonist in the injured spinal cord using an organotypic slice culture. Spinal cords from 6-week-old mice were cut into transverse slices of 400 μm and injured using a weight dropped. GW0742 was applied at 10 μM 1 hour before injury.

*Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy

Dipartimento di Farmacologia Sperimentale, Università di Napoli “Federico II,” Italy

IRCCS Centro Neurolesi “Bonino-Pulejo,” Messina, Italy.

Address correspondence and reprint requests to Salvatore Cuzzocrea, PhD, Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy; E-mail: salvator@unime.it

Acknowledgment date: December 14, 2010. Revision date: April 13, 2011. Acceptance date: April 25, 2011.

The device(s)/drug(s) that is/are the subject of the manuscript is/are not intended for human use.

Foundation funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Supported by a grant from the IRCCS Centro Neurolesi “Bonino-Pulejo,” Messina, Italy.

© 2012 Lippincott Williams & Wilkins, Inc.