title: The NAMPT inhibitor FK866 reverts the damage in spinal cord injury.
abstract: BACKGROUND
  Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting.
  
  
  METHODS
  We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI.
  
  
  RESULTS
  Twenty-four hr following induction of SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in TNF-α, IL-1β, PAR, NAMPT, Bax, MPO activity, NF-κB activation, astrogliosis and microglial activation was observed. Meanwhile, the expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased significantly. Treatment with FK866 (10 mg/kg), the best known and characterized NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved perilesional gray and white matter, restored anti-apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF-α, IL-1β, Bax expression and NF-κB activity.We show for the first time that FK866, a specific inhibitor of NAMPT, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. We also show that NAMPT protein levels are increased upon SCI in the perilesional area which can be corrected by administration of FK866.
  
  
  CONCLUSIONS
  Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors.
authors.affiliation: 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. salvator@unime.it
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Daniela
authors.initials: D
authors.lastname: Impellizzeri
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Gohar
authors.initials: G
authors.lastname: Fakhfouri
authors.forename: Reza
authors.initials: R
authors.lastname: Rahimian
authors.forename: Cristina
authors.initials: C
authors.lastname: Travelli
authors.forename: Gian Cesare
authors.initials: GC
authors.lastname: Tron
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000178:Acrylamides / Q000494:pharmacology / Q000627:therapeutic use*; D000429:Alcohol Oxidoreductases; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D007796:Laminectomy; D008297:Male; D051379:Mice; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D016622:Silver Staining; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D013997:Time Factors
chemical_list: D000178:Acrylamides; D016207:Cytokines; D004791:Enzyme Inhibitors; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D016328:NF-kappa B; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D010880:Piperidines; D000429:Alcohol Oxidoreductases; C110191:phenylacetaldehyde reductase; D009195:Peroxidase; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse