Iptakalim protects against ischemic injury by improving neurovascular unit function in the mouse brain
Iptakalim protects against ischemic injury by improving neurovascular unit function in the mouse brain
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DOI：
10.1111/1440-1681.12426
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发表时间：
2015-07
影响因子：
2.9
通讯作者：
J. Ji;Hui Yan;Zheng-Zhen Chen;Zhan Zhao;Dan-dan Yang;Xiulan Sun;Yong-ping Shi
中科院分区：
文献类型：
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作者：
J. Ji;Hui Yan;Zheng-Zhen Chen;Zhan Zhao;Dan-dan Yang;Xiulan Sun;Yong-ping Shi
据报道，新型ATP敏感性钾（K-ATP）通道开放剂埃他卡林（IPT）可减轻大鼠缺血性神经元损伤。然而，神经保护的机制仍有待充分阐明。本研究的结果表明，与假手术小鼠相比，大脑中动脉闭塞诱导的缺血小鼠表现出更高的死亡率和更多的神经功能缺损，以及更大的梗死体积。此外，研究发现，缺血激活了CA 1神经元周围的星形胶质细胞，增加了D-丝氨酸的表达，诱导了更大的小胶质细胞活化，伴随着更高的肿瘤坏死因子α（TNF-α）的产生，并导致小鼠内皮细胞中基质金属蛋白酶9（MMP-9）的更高表达。IPT预处理可明显减轻小鼠的神经功能缺损，缩小梗死体积。IPT治疗可减少MMP-9分泌，通过降低D-丝氨酸和升高连接蛋白43表达来抑制星形胶质细胞活化。IPT还抑制了小胶质细胞活化，并减少了TNF-α的产生。总之，K-ATP通道开放剂可以改善神经血管单元的功能并防止缺血性损伤。这些发现表明，靶向K-ATP通道为中风提供了一种有前途的治疗方法。
It has been reported that the novel ATP‐sensitive potassium (K‐ATP) channel opener iptakalim (IPT) decreases ischemic neuronal damage in rats. However, the mechanisms underlying neuroprotection are still to be fully elucidated. The results of this study showed that mice with ischemia induced by middle cerebral artery occlusion exhibited higher mortality and more neurological deficits, as well as larger infarct volume, compared with sham mice. Moreover, it was found that ischemia activated astrocytes surrounding CA1 neurons with an increased expression of D‐serine, induced greater microglial activation accompanied by higher tumor necrosis factor alpha (TNF‐α) production, and caused higher expressions of matrix metalloproteinase 9 (MMP‐9) in the endothelial cells of mice. Pretreatment with IPT significantly attenuated the neurological deficits and decreased the infarct volume in mice. IPT treatment could decrease MMP‐9 secretion, inhibit astrocytic activation with decreasing D‐serine and elevating connexin43 expression. Microglial activation was also inhibited and TNF‐α production was decreased by IPT. Taken together, a K‐ATP channel opener may improve the function of neurovascular unit and protect against ischemic injury. These findings suggest that targeting K‐ATP channels provides a promising therapeutic approach for stroke.