期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 31, 期 12, 页码 2363-2374出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2011.101
关键词
inflammation; KCa3.1; microglia potassium channels; middle cerebral artery occlusion with reperfusion; MCAO; TRAM-34
资金
- American Heart Association [0465140Y]
- NIH [RO1 GM076063]
- American Heart Association Western States Affiliate [09POST2260973]
Microglia and brain infiltrating macrophages significantly contribute to the secondary inflammatory damage in the wake of ischemic stroke. Here, we investigated whether inhibition of KCa3.1 (IKCa1/KCNN4), a calcium-activated K+ channel that is involved in microglia and macrophage activation and expression of which increases on microglia in the infarcted area, has beneficial effects in a rat model of ischemic stroke. Using an HPLC/MS assay, we first confirmed that our small molecule KCa3.1 blocker TRAM-34 effectively penetrates into the brain and achieves micromolar plasma and brain concentrations after intraperitoneal injection. Then, we subjected male Wistar rats to 90 minutes of middle cerebral artery occlusion (MCAO) and administered either vehicle or TRAM-34 (10 or 40 mg/kg intraperitoneally twice daily) for 7 days starting 12 hours after reperfusion. Both compound doses reduced infarct area by similar to 50% as determined by hematoxylin & eosin staining on day 7 and the higher dose also significantly improved neurological deficit. We further observed a significant reduction in ED1(+)-activated microglia and TUNEL-positive neurons as well as increases in NeuN(+) neurons in the infarcted hemisphere. Our findings suggest that KCa3.1 blockade constitutes an attractive approach for the treatment of ischemic stroke because it is still effective when initiated 12 hours after the insult. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 2363-2374; doi:10.1038/jcbfm.2011.101; published online 13 July 2011
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