Research ReportChemokine-related gene expression in the brain following ischemic stroke: No role for CXCR2 in outcome

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.

Research Highlights►Several chemokine-related genes are upregulated in the brain after stroke. ►CXCR2 and its ligands CXCL1 and CXCL2 are markedly upregulated. ►A CXCR2 antagonist prevented changes in gene expression and neutrophil infiltration. ►However, the CXCR2 antagonist did not improve functional outcome after stroke.