TY  - EJOU
AU  - Garau, Angela 
AU  - Bertini, Riccardo 
AU  - Mosca, Marco 
AU  - Bizzarri, Cinzia 
AU  - Anacardio, Roberto 
AU  - Triulzi, Sara 
AU  - Allegretti, Marcello 
AU  - Ghezzi, Pietro 
AU  - Villa, Pia 

TI  - Development of a systemically-active dual CXCR1/CXCR2 allosteric inhibitor and its efficacy in a model of transient cerebral ischemia in the rat
T2  - European Cytokine Network

PY  - 2006
VL  - 17
IS  - 1
SN  - 1952-4005

AB  - The chemokine receptors CXCR1 and CXCR2 present on polymorphonuclear neutrophils (PMN),
bind the chemokine CXC ligand 8 (CXCL8)/interleukin-8 (IL-8), and have a key role in PMN recruitment in
inflammation. Based on the structure of reparixin, a small-molecular-weight allosteric inhibitor of CXCR1, we
designed a dual inhibitor of CXCR1 and CXCR2 with a longer in vivo half-life, DF2156A. This molecule inhibited
human and rat PMN migration in response to CXCR1 and CXCR2 ligands and showed an elimination half-life
following i.v. administration, of 19 hours. In a rat model of cerebral ischemia/reperfusion induced by temporary
(90 min) middle cerebral artery (MCA) occlusion, DF2156A (8 mg-kg, i.v., at the time of reperfusion) decreased
the PMN infiltrate, infarct size and significantly improved neurological function. These results indicate that
CXCR1/CXCR2 and their ligands have a role in the inflammatory component of cerebral ischemia, and that these
pathways represent an important pharmacological target.
KW  - chemokines
KW  -  cerebral ischemia
KW  -  neutrophils
KW  -  inflammation
KW  -  anti-inflammatory drugs

DO  -