@Article{,
AUTHOR = {Angela Garau, Riccardo Bertini, Marco Mosca, Cinzia Bizzarri, Roberto Anacardio, Sara Triulzi, Marcello Allegretti, Pietro Ghezzi, Pia Villa},
TITLE = {Development of a systemically-active dual CXCR1/CXCR2 allosteric inhibitor and its efficacy in a model of transient cerebral ischemia in the rat},
JOURNAL = {European Cytokine Network},
VOLUME = {17},
YEAR = {2006},
NUMBER = {1},
PAGES = {35--41},
URL = {http://www.techscience.com/ECN/v17n1/66166},
ISSN = {1952-4005},
ABSTRACT = {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.},
DOI = {}
}