Chemokine-related gene expression in the brain following ischernic stroke: No role for CXCR2 in outcome
Chemokine-related gene expression in the brain following ischernic stroke: No role for CXCR2 in outcome
复制标题
DOI：
10.1016/j.brainres.2010.11.087
复制
发表时间：
2011-02-04
期刊：
影响因子：
2.9
通讯作者：
Sobey, Christopher G.
中科院分区：
文献类型：
--
作者：
Brait, Vanessa H.;Rivera, Jennifer;Sobey, Christopher G.
本研究旨在确定急性卒中治疗的潜在靶点，这些靶点可以在超过目前重组组织纤溶酶原激活剂临床给药的4.5小时时限后立即利用。我们使用PCR阵列初步筛选脑卒中后4，24和72小时的几个趋化因子相关基因的时间表达谱。我们发现，在24或72小时，中性粒细胞CXCR2受体以及CXCL 1和CXCL 2的mRNA大幅增加（> 10倍），CXCL 1和CXCL 2是单核细胞和中性粒细胞表达的两种趋化因子配体，通过CXCR2具有强中性粒细胞趋化活性。然后，我们测试了CXCR2拮抗剂作为治疗剂的功效。在再灌注时开始用载体（1%DMSO）或SB 225002（每天2mg/kg，ip）处理小鼠，并且我们评估了趋化因子基因表达、中性粒细胞浸润以及中风结果的功能和组织学终点。在SB225002处理的小鼠中，24小时后CXCL1、CXCL2和CXCR2的表达水平显著降低至接近正常水平。与溶剂处理的小鼠相比，SB225002处理的小鼠中髓过氧化物酶阳性细胞浸润显著减少，并且与假手术小鼠中的水平相似。然而，尽管SB 225002明显拮抗缺血性脑中CXCR2与其趋化因子配体之间的相互作用，但用SB 225002或载体处理的小鼠在72 h时具有相似的运动障碍和梗死体积。因此，SB225002给药后CXC趋化因子亚家族基因的表达减少和嗜中性粒细胞相关浸润并没有改善脑缺血再灌注后的结果。因此，CXCR2拮抗剂不太可能成为缺血性卒中的潜在治疗方法。(C)2010爱思唯尔有限公司版权所有。
This study sought to identify potential targets for acute stroke therapy that can be exploited pharmacologically beyond the current 4.5 h time limit for clinical administration of recombinant tissue-plasminogen activator. We used PCR arrays to initially screen the temporal expression profiles of several chemokine-related genes in the brain at 4, 24 and 72 h after stroke. We identified large increases (>10-fold) in mRNA at 24 or 72 h for the neutrophil CXCR2 receptor, and for CXCL1 and CXCL2-two chemokine ligands expressed by monocytes and neutrophils with strong neutrophil chemoattractant activity via CXCR2. We then tested the efficacy of a CXCR2 antagonist as a therapeutic. Mice were treated with vehicle (1% DMSO) or SB225002 (2 mg/kg per day, ip) commencing at reperfusion, and we evaluated chemokine gene expression, neutrophil infiltration and functional and histological endpoints of stroke outcome. Expression levels of CXCL1, CXCL2 and CXCR2 after 24 h were markedly reduced to near normal levels in SB225002-treated mice. Myeloperoxidase-positive cell infiltration was significantly reduced in SB225002-treated mice compared with vehicle-treated mice, and was similar to levels in sham-operated mice. However, although SB225002 evidently antagonised the interaction between CXCR2 and its chemokine ligands in the ischemic brain, mice treated with either SB225002 or vehicle had similar motor impairment and infarct volume at 72 h. Thus, the reduced expression of CXC chemokine subfamily genes and neutrophil-related infiltration following SB225002 administration did not improve outcome after cerebral ischemia-reperfusion. CXCR2 antagonists are therefore unlikely to be a potential therapy for ischemic stroke. (C) 2010 Elsevier B.V. All rights reserved.