Evidence for the role of mitogen-activated protein kinase signaling pathways in the development of spinal cord injury.
Mitogen-activated protein kinase (MAPK) signaling pathways involve two closely related MAPKs, known as extracellular signal-regulated kinase (ERK)1 and ERK2. The aim of the present study was to evaluate the contribution of MAPK3/MAPK1 in the secondary damage in experimental spinal cord injury (SCI) in mice. To this purpose, we used 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059), which is an inhibitor of MAPK3/MAPK1. Spinal cord trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, and apoptosis. PD98059 treatment (10 mg/kg i.p.) at 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) phospho-ERK1/2 expression, and 6) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, Fas ligand, Bax, and Bcl-2 expression). Moreover, PD98059 significantly ameliorated the recovery of limb function (evaluated by motor recovery score) in a dose-dependent manner. Taken together, our results clearly demonstrate that PD98059 treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.
Genovese
Tiziana
T
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario Via C. Valeria-Gazzi, 98100 Messina, Italy.
Esposito
Emanuela
E
Mazzon
Emanuela
E
Muià
Carmelo
C
Di Paola
Rosanna
R
Meli
Rosaria
R
Bramanti
Placido
P
Cuzzocrea
Salvatore
S
D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020556:Neutrophil Infiltration; D013116:Spinal Cord; D013119:Spinal Cord Injuries / Q000209:etiology* / Q000276:immunology / Q000473:pathology
D016207:Cytokines; D004791:Enzyme Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3