Delayed neuronal preconditioning by NS1619 is independent of calcium activated potassium channels
Delayed neuronal preconditioning by NS1619 is independent of calcium activated potassium channels
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DOI：
10.1111/j.1471-4159.2007.05210.x
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发表时间：
2008-05-01
影响因子：
4.7
通讯作者：
Busija, David W.
中科院分区：
文献类型：
--
作者：
Gaspar, Tamas;Katakam, Prasad;Busija, David W.
1,3-二氢-1-[2-羟基-5-（三氟甲基）苯基]-5-（三氟甲基）- 2h -苯并咪唑-2- 1 （NS1619）是大电导Ca2+活化钾（BKCa）通道的有效激活剂，已被证明可诱导心脏预适应（PC）。本研究的目的是测试NS1619在大鼠皮层神经元培养中对氧-葡萄糖剥夺、H2O2或谷氨酸兴奋毒性的延迟PC效应。我们还研究了其对活性氧（ROS）生成以及线粒体和质膜电位的作用。此外，我们还检测了PI3K信号通路的激活以及NS1619对caspase-3/7的影响。NS1619剂量依赖性地保护细胞免受毒性损伤，这种保护被一种超氧化物歧化酶模拟物和一种PI3K拮抗剂完全阻断，但不被BKCa通道抑制剂阻断。NS1619的应用增加ROS的产生，使分离的线粒体去极化，使神经元细胞膜超极化，激活PI3K信号级联。然而，BKCa通道阻滞剂只对细胞膜电位有拮抗作用。NS1619抑制了capase-3/7的活化。综上所述，NS1619是一种有效的延迟神经元PC诱导剂。然而，神经保护作用似乎独立于细胞膜和线粒体BKCa通道。相反，它是ROS生成、PI3K通路激活和caspase激活抑制的结果。
1,3-Dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619), a potent activator of the large conductance Ca2+ activated potassium (BKCa) channel, has been demonstrated to induce preconditioning (PC) in the heart. The aim of our study was to test the delayed PC effect of NS1619 in rat cortical neuronal cultures against oxygen-glucose deprivation, H2O2, or glutamate excitotoxicity. We also investigated its actions on reactive oxygen species (ROS) generation, and on mitochondrial and plasma membrane potentials. Furthermore, we tested the activation of the phosphoinositide 3-kinase (PI3K) signaling pathway, and the effect of NS1619 on caspase-3/7. NS1619 dose-dependently protected the cells against the toxic insults, and the protection was completely blocked by a superoxide dismutase mimetic and a PI3K antagonist, but not by BKCa channel inhibitors. Application of NS1619 increased ROS generation, depolarized isolated mitochondria, hyperpolarized the neuronal cell membrane, and activated the PI3K signaling cascade. However, only the effect on the cell membrane potential was antagonized by BKCa channel blockers. NS1619 inhibited the activation of capase-3/7. In summary, NS1619 is a potent inducer of delayed neuronal PC. However, the neuroprotective effect seems to be independent of cell membrane and mitochondrial BKCa channels. Rather it is the consequence of ROS generation, activation of the PI3K pathway, and inhibition of caspase activation.