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首页> 外文期刊>Brain research >A novel voltage-sensitive Na(+) and Ca(2+) channel blocker, NS-7, prevents suppression of cyclic AMP-dependent protein kinase and reduces infarct area in the acute phase of cerebral ischemia in rat.
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A novel voltage-sensitive Na(+) and Ca(2+) channel blocker, NS-7, prevents suppression of cyclic AMP-dependent protein kinase and reduces infarct area in the acute phase of cerebral ischemia in rat.

机译：新型的电压敏感的Na（+）和Ca（2+）通道阻滞剂NS-7可以抑制环状AMP依赖性蛋白激酶的抑制，并减少大鼠脑缺血急性期的梗塞面积。

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Binding of cyclic AMP to the regulatory subunit of cyclic AMP-dependent protein kinase (PKA) is an essential step in cyclic AMP-mediated intracellular signal transduction. This binding is, however, rapidly inhibited in the acute phase of cerebral ischemia, indicating that the signal transduction via PKA is very vulnerable to ischemia, although this signal pathway is very important for neuronal survival in the brain. Several lines of evidence suggest that the activation of voltage-sensitive Na+ and Ca(2+) channels is an important mediator of acute ischemic brain damage. In the present study, therefore, we examined the effect of a novel Na+ and Ca(2+) channel blocker, NS-7 (4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride), on changes in the binding activity of PKA to cyclic AMP in permanent focal cerebral ischemia, which was induced by occlusion of the middle cerebral artery by the intraluminal suture method for 5 h in the rat. NS-7 (1 mg/kg) or saline was intravenously infused 5 min after occlusion. The binding activity of PKA to cyclic AMP and local cerebral blood flow were assessed by the in vitro [(3)H]cyclic AMP binding and the [(14)C]iodoantipyrine methods, respectively. NS-7 significantly suppressed inhibition of the binding activity of PKA to cyclic AMP in the ischemic regions such as the frontal and parietal cortices and the medial region of the caudate-putamen without affecting cerebral blood flow or arterial blood pressure. Infarct area measured in the brain slices stained with cresyl violet was significantly smaller in animals treated with NS-7 than in those treated with saline. Blockade of voltage-sensitive Na+ and Ca(2+) channels by NS-7 was expected to reduce ischemia-induced depolarization and thus prevent a massive formation of free radicals, which is known to inhibit the binding activity of PKA to cyclic AMP. These data clearly indicate that NS-7 provides very efficient neuroprotection in the acute phase of cerebral ischemia, and sustains the normal function of PKA.
机译：环状AMP与环状AMP依赖性蛋白激酶（PKA）的调节亚基的结合是环状AMP介导的细胞内信号转导的重要步骤。但是，这种结合在脑缺血的急性期被迅速抑制，这表明通过PKA进行的信号转导非常容易受到局部缺血的影响，尽管该信号通路对于大脑中神经元的存活非常重要。几条证据表明，电压敏感的Na +和Ca（2+）通道的激活是急性缺血性脑损伤的重要介质。因此，在本研究中，我们检查了新型Na +和Ca（2+）通道阻滞剂NS-7（4-（4-氟苯基）-2-甲基-6-（5-哌啶基戊氧基）嘧啶盐酸盐）的作用在大鼠局灶性脑缺血中，PKA与环状AMP的结合活性发生了变化，这是通过腔内缝合法将大鼠大脑中动脉闭塞5 h引起的。闭塞后5分钟静脉输注NS-7（1 mg / kg）或生理盐水。分别通过体外[（3）H]环AMP结合和[（14）C]碘安替比林方法评估PKA对环AMP的结合活性和局部脑血流。 NS-7显着抑制了缺血区域（例如额叶和顶叶皮层以及尾状壳状核膜的中间区域）中PKA与环状AMP的结合活性的抑制，而没有影响脑血流量或动脉血压。 NS-7处理动物的脑片中，被甲酚紫染色的梗死面积显着小于生理盐水处理的动物。预期通过NS-7阻断电压敏感的Na +和Ca（2+）通道可减少局部缺血引起的去极化，从而防止自由基的大量形成，而自由基的形成可抑制PKA与环状AMP的结合活性。这些数据清楚地表明，NS-7在脑缺血的急性期提供了非常有效的神经保护作用，并维持了PKA的正常功能。

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