Abstract
Background and purpose: Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 inhibitor, DF 2162, in adjuvant-induced polyarthritis (AIA) were investigated. Experimental approach: A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti-TNF or anti-CINC-1 antibodies on joint inflammation and local production of cytokines and chemokines. Key results: DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg -1, twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL-1β, CCL2 and CCL5. The effects of DF2162 were similar to those of anti-TNF, and more effective than those of anti-CINC-1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction. Conclusions and implications: DF 2162, a novel orally-active non-competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti-TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.
| Original language | English |
|---|---|
| Pages (from-to) | 992-1002 |
| Number of pages | 11 |
| Journal | British Journal of Pharmacology |
| Volume | 153 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Mar 2008 |
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Keywords
- Chemokine receptor
- CXCR2
- Experimental arthritis
- Neutrophil
- Rheumatoid arthritis
- TNF-α
ASJC Scopus subject areas
- Pharmacology
Cite this
Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats. / 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.
In: British Journal of Pharmacology, Vol. 153, No. 5, 03.2008, p. 992-1002.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats
AU - Barsante, M. M.
AU - Cunha, T. M.
AU - Allegretti, M.
AU - Cattani, F.
AU - Policani, F.
AU - Bizzarri, C.
AU - Tafuri, W. L.
AU - Poole, S.
AU - Cunha, F. Q.
AU - Bertini, R.
AU - Teixeira, M. M.
PY - 2008/3
Y1 - 2008/3
N2 - Background and purpose: Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 inhibitor, DF 2162, in adjuvant-induced polyarthritis (AIA) were investigated. Experimental approach: A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti-TNF or anti-CINC-1 antibodies on joint inflammation and local production of cytokines and chemokines. Key results: DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg -1, twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL-1β, CCL2 and CCL5. The effects of DF2162 were similar to those of anti-TNF, and more effective than those of anti-CINC-1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction. Conclusions and implications: DF 2162, a novel orally-active non-competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti-TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.
AB - Background and purpose: Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 inhibitor, DF 2162, in adjuvant-induced polyarthritis (AIA) were investigated. Experimental approach: A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti-TNF or anti-CINC-1 antibodies on joint inflammation and local production of cytokines and chemokines. Key results: DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg -1, twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL-1β, CCL2 and CCL5. The effects of DF2162 were similar to those of anti-TNF, and more effective than those of anti-CINC-1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction. Conclusions and implications: DF 2162, a novel orally-active non-competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti-TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.
KW - Chemokine receptor
KW - CXCR2
KW - Experimental arthritis
KW - Neutrophil
KW - Rheumatoid arthritis
KW - TNF-α
UR - http://www.scopus.com/inward/record.url?scp=40149101133&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=40149101133&partnerID=8YFLogxK
U2 - 10.1038/sj.bjp.0707462
DO - 10.1038/sj.bjp.0707462
M3 - Article
C2 - 17891165
AN - SCOPUS:40149101133
VL - 153
SP - 992
EP - 1002
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 5
ER -