Lorenzo Di Cesare Mannelli1, Laura Micheli2, Lorenzo Cinci2, Mario Maresca2, Claudia Vergelli3, Alessandra Pacini4, Mark T Quinn5, Maria Paola Giovannoni3, Carla Ghelardini2. 1. Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section lorenzo.mannelli@unifi.it. 2. Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section. 3. Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmaceutical and Nutraceutical Section. 4. Department of Experimental and Clinical Medicine, DMSC, Anatomy and Histology Section, University of Florence, Florence, Italy. 5. Department of Microbiology and Immunology, Montana State University, Bozeman, MT, USA.
Abstract
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVES: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 RApatients 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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: Letizia Crocetti; Maria Paola Giovannoni; Igor A Schepetkin; Mark T Quinn; Andrei I Khlebnikov; Agostino Cilibrizzi; Vittorio Dal Piaz; Alessia Graziano; Claudia Vergelli Journal: Bioorg Med Chem Date: 2011-07-07 Impact factor: 3.641
Authors: Letizia Crocetti; Claudia Vergelli; Gabriella Guerrini; Niccolò Cantini; Liliya N Kirpotina; Igor A Schepetkin; Mark T Quinn; Carmen Parisio; Lorenzo Di Cesare Mannelli; Carla Ghelardini; Maria Paola Giovannoni Journal: Bioorg Chem Date: 2020-04-28 Impact factor: 5.275
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