Treatment with DF 2162, a non-competitive allosteric inhibitor of CXCR1/2, diminishes neutrophil influx and inflammatory hypernociception in mice

被引:83
作者
Cunha, T. M. [2 ]
Barsante, M. M. [1 ]
Guerrero, A. T. [2 ]
Verri, W. A., Jr. [2 ]
Ferreira, S. H. [2 ]
Coelho, F. M. [1 ]
Bertini, R. [3 ]
Di Giacinto, C. [3 ]
Allegretti, M. [3 ]
Cunha, F. Q. [2 ]
Teixeira, M. M. [1 ]
机构
[1] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, BR-31270901 Belo Horizonte, MG, Brazil
[2] Univ Ribeirao Preto, Fac Med, Dept Pharmacol, Sao Paulo, Brazil
[3] Dompe Pharma Spa, Dept Preclin Pharmacol, Laquila, Italy
关键词
chemokines; CXCR1/2; arthritis; neutrophil; TNF-alpha; hyperalgesia;
D O I
10.1038/bjp.2008.94
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background and purpose: Neutrophil migration into tissues is involved in the genesis of inflammatory pain. Here, we addressed the hypothesis that the effect of CXC chemokines on CXCR1/2 is important to induce neutrophil migration and inflammatory hypernociception. Experimental approach: Mice were treated with a non-competitive allosteric inhibitor of CXCR1/2, DF 2162, and neutrophil influx and inflammatory hypernociception were assessed by myeloperoxidase assay and electronic pressure meter test, respectively, in various models of inflammation. Key results: DF 2162 inhibited neutrophil chemotaxis induced by CXCR1/2 ligands but had no effect on CXCL8 binding to neutrophils. A single mutation of the allosteric site at CXCR1 abrogated the inhibitory effect of DF 2162 on CXCL-8-induced chemotaxis. Treatment with DF 2162 prevented influx of neutrophils and inflammatory hypernociception induced by CXCL1 in a dose-dependent manner. The compound inhibited neutrophil influx and inflammatory hypernociception induced by carrageenan, lipopolysaccharide and zymosan, but not hypernociception induced by dopamine and PGE(2). DF 2162 had a synergistic effect with indomethacin or the absence of TNFR1 to abrogate carrageenan-induced hypernociception. Treatment with DF 2162 diminished neutrophil influx, oedema formation, disease score and hypernociception in collagen-induced arthritis. Conclusions and implications: CXCR1/2 mediates neutrophil migration and is involved in the cascade of events leading to inflammatory hypernociception. In addition to modifying fundamental pathological processes, non-competitive allosteric inhibitors of CXCR1/2 may have the additional benefit of providing partial relief for pain and, hence, may be a valid therapeutic target for further studies aimed at the development of new drugs for the treatment of rheumatoid arthritis.
引用
收藏
页码:460 / 470
页数:11
相关论文
共 41 条
[1]   Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats [J].
Barsante, M. M. ;
Cunha, T. M. ;
Allegretti, M. ;
Cattani, F. ;
Policani, F. ;
Bizzarri, C. ;
Tafuri, W. L. ;
Poole, S. ;
Cunha, F. Q. ;
Bertini, R. ;
Teixeira, M. M. .
BRITISH JOURNAL OF PHARMACOLOGY, 2008, 153 (05) :992-1002
[2]   Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury [J].
Bertini, R ;
Allegretti, M ;
Bizzarri, C ;
Moriconi, A ;
Locati, M ;
Zampella, G ;
Cervellera, MN ;
Di Cioccio, V ;
Cesta, MC ;
Galliera, E ;
Martinez, FO ;
Di Bitondo, R ;
Troiani, G ;
Sabbatini, V ;
D'Anniballe, G ;
Anacardio, R ;
Cutrin, JC ;
Cavalieri, B ;
Mainiero, F ;
Strippoli, R ;
Villa, P ;
Di Girolamo, M ;
Martin, F ;
Gentile, M ;
Santoni, A ;
Corda, D ;
Poli, G ;
Mantovani, A ;
Ghezzi, P ;
Colotta, F .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (32) :11791-11796
[3]   Neutrophils-derived peroxynitrite contributes to acute hyperalgesia and cell influx in zymosan arthritis [J].
Bezerra, Mirna M. ;
Brain, Susan D. ;
Giro, Virginia C. C. ;
Greenacre, Stan ;
Keeble, Julie ;
Rocha, Francisco A. C. .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2007, 374 (04) :265-273
[4]   Selective inhibition of interleukin-8-induced neutrophil chemotaxis by ketoprofen isomers [J].
Bizzarri, C ;
Pagliei, S ;
Brandolini, L ;
Mascagni, P ;
Caselli, G ;
Transidico, P ;
Sozzani, S ;
Bertini, R .
BIOCHEMICAL PHARMACOLOGY, 2001, 61 (11) :1429-1437
[5]   ELR+ CXC chemokines and their receptors (CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets [J].
Bizzarri, Cinzia ;
Beccari, Andrea Rosario ;
Bertini, Riccardo ;
Cavicchia, Michela Rita ;
Giorgini, Simona ;
Allegretti, Marcello .
PHARMACOLOGY & THERAPEUTICS, 2006, 112 (01) :139-149
[6]   Regulation of chemotactic and proadhesive responses to chemoattractant receptors by RGS (Regulator of G-protein Signaling) family members [J].
Bowman, EP ;
Campbell, JJ ;
Druey, KM ;
Scheschonka, A ;
Kehrl, JH ;
Butcher, EC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (43) :28040-28048
[7]  
BOZIC CR, 1994, J BIOL CHEM, V269, P29355
[8]   MEASUREMENT OF CUTANEOUS INFLAMMATION - ESTIMATION OF NEUTROPHIL CONTENT WITH AN ENZYME MARKER [J].
BRADLEY, PP ;
PRIEBAT, DA ;
CHRISTENSEN, RD ;
ROTHSTEIN, G .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1982, 78 (03) :206-209
[9]   Small molecule antagonists of the CXCR2 and CXCR1 chemokine receptors as therapeutic agents for the treatment of inflammatory diseases [J].
Busch-Petersen, Jakob .
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2006, 6 (13) :1345-1352
[10]   Neutrophil recruitment in the reperfused-injured rat liver was effectively attenuated by repertaxin, a novel allosteric noncompetitive inhibitor of CXCL8 receptors:: A therapeutic approach for the treatment of post-ischemic hepatic syndromes [J].
Cavalieri, B ;
Mosca, M ;
Ramadori, P ;
Perrelli, MG ;
De Simone, L ;
Colotta, F ;
Bertini, R ;
Poli, G ;
Cutrìn, JC .
INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY, 2005, 18 (03) :475-486