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Chemokine-related gene expression in the brain following ischemic stroke: no role for CXCR2 in outcome.
Brain Res. 2011 Feb 04; 1372:169-79.BR

Abstract

This study sought to identify potential targets for acute stroke therapy that can be exploited pharmacologically beyond the current 4.5h 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 72h after stroke. We identified large increases (>10-fold) in mRNA at 24 or 72h 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 (2mg/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 24h 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 72h. 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.

Authors+Show Affiliations

Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21138735

Citation

Brait, Vanessa H., et al. "Chemokine-related Gene Expression in the Brain Following Ischemic Stroke: No Role for CXCR2 in Outcome." Brain Research, vol. 1372, 2011, pp. 169-79.
Brait VH, Rivera J, Broughton BR, et al. Chemokine-related gene expression in the brain following ischemic stroke: no role for CXCR2 in outcome. Brain Res. 2011;1372:169-79.
Brait, V. H., Rivera, J., Broughton, B. R., Lee, S., Drummond, G. R., & Sobey, C. G. (2011). Chemokine-related gene expression in the brain following ischemic stroke: no role for CXCR2 in outcome. Brain Research, 1372, 169-79. https://doi.org/10.1016/j.brainres.2010.11.087
Brait VH, et al. Chemokine-related Gene Expression in the Brain Following Ischemic Stroke: No Role for CXCR2 in Outcome. Brain Res. 2011 Feb 4;1372:169-79. PubMed PMID: 21138735.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chemokine-related gene expression in the brain following ischemic stroke: no role for CXCR2 in outcome. AU - Brait,Vanessa H, AU - Rivera,Jennifer, AU - Broughton,Brad R S, AU - Lee,Seyoung, AU - Drummond,Grant R, AU - Sobey,Christopher G, Y1 - 2010/12/04/ PY - 2010/10/28/received PY - 2010/11/19/revised PY - 2010/11/25/accepted PY - 2010/12/9/entrez PY - 2010/12/9/pubmed PY - 2011/5/4/medline SP - 169 EP - 79 JF - Brain research JO - Brain Res. VL - 1372 N2 - This study sought to identify potential targets for acute stroke therapy that can be exploited pharmacologically beyond the current 4.5h 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 72h after stroke. We identified large increases (>10-fold) in mRNA at 24 or 72h 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 (2mg/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 24h 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 72h. 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. SN - 1872-6240 UR - https://www.unboundmedicine.com/medline/citation/21138735/Chemokine_related_gene_expression_in_the_brain_following_ischemic_stroke:_no_role_for_CXCR2_in_outcome_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(10)02600-4 DB - PRIME DP - Unbound Medicine ER -