title: Development of a systemically-active dual CXCR1/CXCR2 allosteric inhibitor and its efficacy in a model of transient cerebral ischemia in the rat.
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.
authors.affiliation: Laboratory of Neuroimmunology, Mario Negri Institute for Pharmacological Research, via Eritrea 62, 20157 Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Garau
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bertini
authors.forename: Marco
authors.initials: M
authors.lastname: Mosca
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bizzarri
authors.forename: Roberto
authors.initials: R
authors.lastname: Anacardio
authors.forename: Sara
authors.initials: S
authors.lastname: Triulzi
authors.forename: Marcello
authors.initials: M
authors.lastname: Allegretti
authors.forename: Pietro
authors.initials: P
authors.lastname: Ghezzi
authors.forename: Pia
authors.initials: P
authors.lastname: Villa
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002465:Cell Movement; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D009504:Neutrophils / Q000378:metabolism*; D051381:Rats; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C511776:2'-((4'-trifluoromethanesulfonyloxy)phenyl)-N-methanesulfonylpropionamide; D016209:Interleukin-8; D018696:Neuroprotective Agents; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides