title: Effects of the neutrophil elastase inhibitor EL-17 in rat adjuvant-induced arthritis.
abstract: Neutrophil elastase (NE), a granule-associated enzyme, participates in connective tissue breakdown and promotes cytokine release and specific receptor activation during various inflammatory diseases like RA. NE is increased in the SF and cartilage of RA patients and represents a target for the development of new therapeutic possibilities. The present research aimed to evaluate the preclinical pharmacological profile of the N-benzoylpyrazole derivative EL-17, a potent and selective NE inhibitor, in a rat model of RA.
  
  
  
  Complete Freund's Adjuvant (CFA) was injected in the tibiotarsal joint and the effect of acute or repeated treatments with EL-17 (1-30 mg/kg by mouth) were evaluated.
  
  
  
  On day 14 after CFA injection, a single administration of EL-17 significantly reduced CFA-dependent hypersensitivity to mechanical noxious stimuli and the postural unbalance related to spontaneous pain. To evaluate the preventive efficacy, EL-17 was administered daily starting from the day of CFA treatment. Behavioural measurements performed on days 7 and 14 showed a progressive efficacy of EL-17 against hypersensitivity to mechanical noxious and non-noxious stimuli, as well as a decrease of hind limb weight-bearing alterations. Histological evaluation of the tibiotarsal joint (day 14) demonstrated significant prevention of articular derangement after EL-17 (30 mg/kg) treatment. The protective effects of EL-17 directly correlated with a complete reversion of the plasma NE activity increase induced by CFA.
  
  
  
  The NE inhibitor EL-17 relieved articular pain after acute administration. Furthermore, repeated treatment reduced the development of hypersensitivity and protected joint tissue, revealing a disease-modifying profile.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section lorenzo.mannelli@unifi.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section.
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cinci
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section.
authors.forename: Mario
authors.initials: M
authors.lastname: Maresca
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmaceutical and Nutraceutical Section.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
authors.affiliation: Department of Experimental and Clinical Medicine, DMSC, Anatomy and Histology Section, University of Florence, Florence, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pacini
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmaceutical and Nutraceutical Section.
authors.forename: Maria
authors.initials: M
authors.lastname: Paola Giovannoni
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D018771:Arthralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D005620:Freund's Adjuvant; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007191:Indazoles / Q000008:administration & dosage*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013640:Tarsal Joints / Q000187:drug effects / Q000503:physiopathology; D016474:Weight-Bearing
chemical_list: D000276:Adjuvants, Immunologic; C000620799:EL-17 compound; D007191:Indazoles; D053491:Proteinase Inhibitory Proteins, Secretory; D011720:Pyrazoles; D005620:Freund's Adjuvant
keywords: CFA; TGF-β; elastase activity; joint derangement; mechanical and thermal hypersensitivity; neutrophil serine proteases; polymorphonuclear neutrophil