title: TNF-alpha blockage in a mouse model of SCI: evidence for improved outcome.
abstract: The aim of our study was to evaluate in vivo the therapeutic efficacy of genetic inhibition of TNF-alpha using TNF-R1 knockout mice in an experimental model of spinal cord trauma. Spinal cord injury was induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. To elucidate whether the observed anti-inflammatory status is related to the inhibition of TNF-alpha, we also investigated the effect of infliximab, a TNF-alpha-soluble receptor construct, on spinal cord damage. Pharmacological and genetic TNF-alpha inhibition significantly reduced the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (evaluated by myeloperoxidase activity), (3) cytokine expression (TNF-alpha), (4) and apoptosis (terminal deoxynucleotidyltransferase-mediated uridine triphosphate end labeling staining, Bax, Bcl-2, and Fas-L expression). In a separate set of experiments, we have also demonstrated that TNF-alpha inhibition significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results demonstrate that inhibition of TNF-alpha reduces the development of inflammation and tissue injury associated with spinal cord trauma, suggesting a possible role of TNF-alpha on the pathogenesis of spinal cord injury.
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Concetta
authors.initials: C
authors.lastname: Crisafulli
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Carmelo
authors.initials: C
authors.lastname: Muià
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism; D000069285:Infliximab; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D009504:Neutrophils / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C494827:Bax protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D053583:Interleukin-1beta; D019253:Proto-Oncogene Proteins c-bcl-2; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D000069285:Infliximab; C505409:Casp3 protein, mouse; D053148:Caspase 3