Garau Angela, Bertini Riccardo, Mosca Marco, Bizzarri Cinzia, Anacardio Roberto, Triulzi Sara, Allegretti Marcello, Ghezzi Pietro, Villa Pia
Laboratory of Neuroimmunology, Mario Negri Institute for Pharmacological Research, via Eritrea 62, 20157 Milan, Italy.
Eur Cytokine Netw. 2006 Mar;17(1):35-41.
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.
存在于多形核中性粒细胞（PMN）上的趋化因子受体CXCR1和CXCR2，可结合趋化因子CXC配体8（CXCL8）/白细胞介素-8（IL-8），并在炎症过程中PMN的募集方面发挥关键作用。基于CXCR1的小分子变构抑制剂瑞帕昔的结构，我们设计了一种体内半衰期更长的CXCR1和CXCR2双重抑制剂DF2156A。该分子可抑制人及大鼠PMN对CXCR1和CXCR2配体的迁移反应，静脉注射给药后的消除半衰期为19小时。在由短暂（90分钟）大脑中动脉（MCA）闭塞诱导的大鼠脑缺血/再灌注模型中，DF2156A（8毫克/千克，静脉注射，再灌注时给药）可减少PMN浸润、梗死面积，并显著改善神经功能。这些结果表明，CXCR1/CXCR2及其配体在脑缺血的炎症成分中起作用，并且这些途径代表了一个重要的药理学靶点。
