Combination of dexamethasone and etanercept reduces secondary damage in experimental spinal cord trauma.
The aim of our study was to evaluate the therapeutic efficacy of combination therapy with etanercept and dexamethasone (DEX) in vivo in experimental murine model of spinal cord trauma, which was 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, and cytokine production followed by recruitment of other inflammatory cells, production of inflammation mediators, tissue damage, apoptosis and disease. Treatment of the mice with etanercept (1.25 mg/kg) and DEX (0.025 mg/kg) when administered as a combination therapy but not as a single treatment significantly reduced the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) infiltration of neutrophils (MPO evaluation), (3) inducible nitric oxide synthase, nitrotyrosine, and cytokines expression (tumor necrosis factor-alpha and interleukin-1 beta), (4) and apoptosis (Terminal deoxynucleotidyltransferase-mediated UTP end labeling staining, Fas-ligand expression and Bax and Bcl-2 expression). In a separate set of experiments we have also clearly demonstrated that the combination therapy significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate for the first time that strategies targeting multiple proinflammatory pathways may be more effective than a single effector molecule for the treatment of spinal cord trauma.
Genovese
T
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.
Mazzon
E
E
Crisafulli
C
C
Esposito
E
E
Di Paola
R
R
Muià
C
C
Di Bella
P
P
Meli
R
R
Bramanti
P
P
Cuzzocrea
S
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D003907:Dexamethasone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D000068800:Etanercept; D007074:Immunoglobulin G / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling / Q000379:methods; D053583:Interleukin-1beta / Q000378:metabolism; D007796:Laminectomy / Q000009:adverse effects; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C494827:Bax protein, mouse; D007074:Immunoglobulin G; D053583:Interleukin-1beta; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C002744:3-nitrotyrosine; D014443:Tyrosine; D003907:Dexamethasone; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D000068800:Etanercept