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The NAMPT Inhibitor FK866 Reverts The Damage In Spinal Cord Injury
Author(s) -
Esposito Emanuela,
Impellizzeri Daniela,
Mazzon Emanuela,
Fakhfouric Gohar,
Rahimian Reza,
Travelli Cristina,
Tron Gian Cesare,
Genazzani Armando A,
Cuzzocrea Salvatore
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.845.2
Subject(s) - astrogliosis , nicotinamide phosphoribosyltransferase , microglia , inflammation , medicine , spinal cord injury , neuroinflammation , palmitoylethanolamide , neuroprotection , pharmacology , proinflammatory cytokine , immunology , cancer research , spinal cord , chemistry , central nervous system , nad+ kinase , biochemistry , receptor , cannabinoid receptor , psychiatry , enzyme , agonist
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. We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI in mice. Twenty‐four hr following SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in cytokines, PAR, NAMPT, Bax, MPO activity, NF‐κB activation, astrogliosis and microglial activation was observed. Meanwhile, levels of neurotrophins and anti‐apoptotic Bcl‐2 significantly decreased. Treatment with FK866 (10 mg/kg), the best characterized NAMPT inhibitor, at 1h and 6h after SCI rescued motor function, preserved prelesional 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 levels and NF‐κB activity. We show for the first time that FK866, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors.