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Evidence for the role of peroxisome proliferator-activated receptor-beta/delta in the development of spinal cord injury.
J Pharmacol Exp Ther. 2010 May; 333(2):465-77.JP

Abstract

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.

Authors+Show Affiliations

Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20176685

Citation

Paterniti, Irene, et al. "Evidence for the Role of Peroxisome Proliferator-activated Receptor-beta/delta in the Development of Spinal Cord Injury." The Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 2, 2010, pp. 465-77.
Paterniti I, Esposito E, Mazzon E, et al. Evidence for the role of peroxisome proliferator-activated receptor-beta/delta in the development of spinal cord injury. J Pharmacol Exp Ther. 2010;333(2):465-77.
Paterniti, I., Esposito, E., Mazzon, E., Galuppo, M., Di Paola, R., Bramanti, P., Kapoor, A., Thiemermann, C., & Cuzzocrea, S. (2010). Evidence for the role of peroxisome proliferator-activated receptor-beta/delta in the development of spinal cord injury. The Journal of Pharmacology and Experimental Therapeutics, 333(2), 465-77. https://doi.org/10.1124/jpet.110.165605
Paterniti I, et al. Evidence for the Role of Peroxisome Proliferator-activated Receptor-beta/delta in the Development of Spinal Cord Injury. J Pharmacol Exp Ther. 2010;333(2):465-77. PubMed PMID: 20176685.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evidence for the role of peroxisome proliferator-activated receptor-beta/delta in the development of spinal cord injury. AU - Paterniti,Irene, AU - Esposito,Emanuela, AU - Mazzon,Emanuela, AU - Galuppo,Maria, AU - Di Paola,Rosanna, AU - Bramanti,Placido, AU - Kapoor,Amar, AU - Thiemermann,Christoph, AU - Cuzzocrea,Salvatore, Y1 - 2010/02/22/ PY - 2010/2/24/entrez PY - 2010/2/24/pubmed PY - 2010/5/11/medline SP - 465 EP - 77 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 333 IS - 2 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/20176685/Evidence_for_the_role_of_peroxisome_proliferator_activated_receptor_beta/delta_in_the_development_of_spinal_cord_injury_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20176685 DB - PRIME DP - Unbound Medicine ER -