The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke
The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke
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DOI：
10.1038/jcbfm.2011.101
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发表时间：
2011-12-01
影响因子：
6.3
通讯作者：
Wulff, Heike
中科院分区：
文献类型：
--
作者：
Chen, Yi-Je;Raman, Girija;Wulff, Heike
小胶质细胞和脑浸润的巨噬细胞在缺血性卒中后的继发性炎症损伤中起重要作用。在这里，我们研究了是否抑制KCa3.1（IKCa 1/KCNN 4），钙激活的K+通道，参与小胶质细胞和巨噬细胞的激活和表达增加的小胶质细胞在梗死区，在缺血性中风的大鼠模型中具有有益的影响。使用HPLC/MS分析，我们首先证实了我们的小分子KCa3.1阻断剂TRAM-34有效地渗透到大脑中，并在腹膜内注射后达到微摩尔血浆和大脑浓度。然后，我们对雄性Wistar大鼠进行90分钟的大脑中动脉闭塞（MCAO），并从再灌注后12小时开始给予溶剂或TRAM-34（10或40 mg/kg，每天两次），持续7天。如在第7天通过苏木精和伊红染色所确定的，两种化合物剂量都使梗塞面积减少了类似于50%，并且较高剂量还显著改善了神经功能缺损。我们进一步观察到ED 1（+）激活的小胶质细胞和TUNEL阳性神经元的显著减少以及梗死半球NeuN（+）神经元的增加。我们的研究结果表明，KCa3.1阻断构成了一个有吸引力的方法治疗缺血性中风，因为它仍然是有效的，当开始后12小时的侮辱。Journal of Cerebral Blood Flow & Metabolism（2011）31，2363-2374; doi：10.1038/jcbfm.2011.101; 2011年7月13日在线发表
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