Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke.
Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke.
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DOI：
10.1002/acn3.513
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发表时间：
2018-03
影响因子：
5.3
通讯作者：
Wulff H
中科院分区：
文献类型：
--
作者：
Chen YJ;Nguyen HM;Maezawa I;Jin LW;Wulff H
电压门控K+通道Kv1.3的抑制剂目前正在开发作为治疗自身免疫性疾病的免疫调节剂。由于Kv1.3也在小胶质细胞上表达，并且已被证明在“M1样”小胶质细胞上特异性上调，因此我们在此测试了脑渗透性小分子Kv1.3抑制剂PAP-1减少缺血/再灌注后继发性炎症损伤的治疗假设。我们使用电生理学和免疫组织化学研究了小胶质细胞Kv1.3的表达，并评估了成年雄性C57 BL/6 J小鼠（60 min MCAO）和成年雄性Wistar大鼠（90 min MCAO）缺氧暴露的器官型海马切片和大脑中动脉闭塞（MCAO）再灌注8天的PAP-1。在两种模型中，PAP-1给药均在再灌注后12小时开始。我们观察了小鼠、大鼠和人类缺血性梗死中激活的小胶质细胞的Kv1.3染色，并发现从梗死半球急性分离的小胶质细胞的Kv1.3电流密度高于从MCAO小鼠对侧半球分离的小胶质细胞。PAP-1与米诺环素一样有效地减少了缺氧暴露的海马切片中的小胶质细胞活化并增加了神经元存活。在小鼠MCAO中，PAP-1剂量依赖性地减少梗死面积，改善神经功能缺损评分，并降低IL-1β和IFN-γ的脑水平，而不影响IL-10和脑源性神经生长因子（BDNF）水平或抑制正在进行的吞噬作用。在大鼠中再现了对梗死面积和神经功能缺损评分的有益作用，从而在第二个物种中提供了确认。我们的研究结果表明，Kv1.3构成了一个有前途的治疗靶点，优先抑制缺血性卒中中的“M1样”炎症小胶质细胞/巨噬细胞功能。
Inhibitors of the voltage‐gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up‐regulated on “M1‐like” microglia, we here tested the therapeutic hypothesis that the brain‐penetrant small‐molecule Kv1.3‐inhibitor PAP‐1 reduces secondary inflammatory damage after ischemia/reperfusion. We studied microglial Kv1.3 expression using electrophysiology and immunohistochemistry, and evaluated PAP‐1 in hypoxia‐exposed organotypic hippocampal slices and in middle cerebral artery occlusion (MCAO) with 8 days of reperfusion in both adult male C57BL/6J mice (60 min MCAO) and adult male Wistar rats (90 min MCAO). In both models, PAP‐1 administration was started 12 h after reperfusion. We observed Kv1.3 staining on activated microglia in ischemic infarcts in mice, rats, and humans and found higher Kv1.3 current densities in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of MCAO mice. PAP‐1 reduced microglia activation and increased neuronal survival in hypoxia‐exposed hippocampal slices as effectively as minocycline. In mouse MCAO, PAP‐1 dose‐dependently reduced infarct area, improved neurological deficit score, and reduced brain levels of IL‐1β and IFN‐γ without affecting IL‐10 and brain‐derived nerve growth factor (BDNF) levels or inhibiting ongoing phagocytosis. The beneficial effects on infarct area and neurological deficit score were reproduced in rats providing confirmation in a second species. Our findings suggest that Kv1.3 constitutes a promising therapeutic target for preferentially inhibiting “M1‐like” inflammatory microglia/macrophage functions in ischemic stroke.
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影响因子：
64.8
作者：
DECOURSEY, TE;CHANDY, KG;CAHALAN, MD
通讯作者：
CAHALAN, MD
影响因子：
6.3
作者：
Chen, Yi-Je;Nguyen, Hai M.;Wulff, Heike
通讯作者：
Wulff, Heike
影响因子：
4.8
作者：
Maezawa, Izumi;Nivison, Mary;Montine, Thomas J.
通讯作者：
Montine, Thomas J.
影响因子：
6.5
作者：
Azam, Philippe;Sankaranarayanan, Ananthakrishnan;Wulff, Heike
通讯作者：
Wulff, Heike
DOI：
10.1097/00004647-200011000-00003
发表时间：
2000-11-01
影响因子：
6.3
作者：
Lyons, SA;Pastor, A;Dirnagl, U
通讯作者：
Dirnagl, U