The newly identified K+ channel blocker talatisamine attenuates beta-amyloid oligomers induced neurotoxicity in cultured cortical neurons
The newly identified K+ channel blocker talatisamine attenuates beta-amyloid oligomers induced neurotoxicity in cultured cortical neurons
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DOI：
10.1016/j.neulet.2012.04.067
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发表时间：
2012-06
影响因子：
2.5
通讯作者：
Yanxia Wang;Mingke Song;Lina Hou;Zhihua Yu;Hongzhuan Chen
中科院分区：
文献类型：
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作者：
Yanxia Wang;Mingke Song;Lina Hou;Zhihua Yu;Hongzhuan Chen
延迟整流钾通道（delayed rectifier K+channels）的上调导致胞浆K+的丢失在β淀粉样蛋白（Aβ）神经毒性中起重要作用。钾离子通道阻断剂，特别是对IKK通道特异性的钾离子通道阻断剂，已被认为是治疗阿尔茨海默病（AD）的一个有吸引力的候选药物。他拉他明是通过虚拟筛选和电生理学鉴定发现的新型IK 1通道阻滞剂。在本研究中，我们研究了他拉替胺对Aβ寡聚体诱导的原代培养皮层神经元细胞毒性的神经保护作用。与Aβ40寡聚体引起的K+丢失相关的神经毒性包括IKdensity增加、细胞膜通透性增加、细胞活力降低和线粒体跨膜电位受损。Aβ40寡聚体孵育后，Bcl-2水平降低，Bax水平升高，Caspase-3和Caspase-9活化。Talatisamine（120μM）和TEA（5 mM）可抑制Aβ40寡聚体引起的IKK增强，通过恢复细胞活力和抑制K+丢失相关的凋亡反应来减弱Aβ寡聚体的细胞毒性。本研究结果提示，他拉替胺可能成为IKchannel阻滞剂的先导化合物，具有神经保护作用。
Loss of cytosolic K+through up-regulated delayed rectifier K+channels play an important role in beta-amyloid (Aβ) induced neurotoxicity. Potent K+channel blocker, particular specific for IKchannels has been suggested as an attractive candidate for the treatment of Alzheimer's disease (AD). Talatisamine is a novel IKchannel blocker discovered by virtual screening and electrophysiological characterization. In the present study, we examined the neuroprotective effect of talatisamine against Aβ oligomers induced cytotoxicity in primarily cultured cortical neurons. The neurotoxicity related to K+loss caused by Aβ40 oligomers included enhanced IKdensity, increased cell membrane permeability, reduced cell viability, and impaired mitochondrial transmembrane potential. Decreased Bcl-2 and increased Bax level, activation of Caspase-3 and Caspase-9 were also observed after Aβ40 oligomers incubation. Talatisamine (120μM) and TEA (5mM) inhibited the enhanced IKcaused by Aβ40 oligomers, attenuated cytotoxicity of Aβ oligomers by restoring cell viability and suppressing K+loss related apoptotic response. Our results suggested that talatisamine may become a leading compound as IKchannel blocker for neuroprotection.