Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
Anesth Analg. 2010 Mar 1;110(3):888-94. doi: 10.1213/ANE.0b013e3181cb5cdd. Epub 2009 Dec 30.
The phosphodiesterase III inhibitor olprinone has been confirmed to improve myocardial function and increase cerebral blood flow; therefore, if olprinone exerts direct neuroprotective effects against global cerebral ischemia to the same degree as cilostazol, olprinone could be useful for cerebral resuscitation after cardiac arrest. We examined whether olprinone directly protected neuronal cells from global cerebral ischemia both in vivo and in vitro.
In a rat model of 10-minute global cerebral ischemia induced by 4-vessel occlusion, 0.3, 3, or 30 microg x kg(-1) x min(-1) olprinone or saline was infused for a periischemic period of 40 minutes (n = 6 for each group). Hippocampal CA1 neuronal cells were then counted 3 days after reperfusion, and the phosphorylation of cyclic adenosine 3'5'-monophosphate response element-binding protein was examined using Western blotting analyses of specimens obtained 15 minutes after reperfusion. In vitro, cultured cerebral neurons were exposed to 4 hours of hypoxia and glucose deprivation and then 24 hours of recovery in the absence or presence of olprinone (10(-11)-10(-5) mol x L(-1)). Cell viability was measured using the Cell Counting Kit-8 (Dojindo Molecular Technologies, Gaithersburg, MD).
In the rat model of global ischemia, the number of surviving CA1 neurons counted under a microscopic field in the 30 microg x kg(-1) x min(-1) olprinone-treated group (49.9 +/- 9.2) was significantly higher than that in the saline infusion control group (7.2 +/- 3.4), and olprinone treatment increased the phosphorylation of cyclic adenosine 3'5'-monophosphate response element-binding protein. The survival fraction of the neuronal cells cultured in the presence of olprinone was also significantly higher than that of cells cultured in the absence of olprinone in a dose-dependent manner.
Our study successfully demonstrated, for the first time, that olprinone had a protective effect on neuronal cells in vitro and in vivo, especially against global cerebral ischemia. These results suggest that olprinone might be useful for the treatment of patients experiencing global cerebral ischemia.
磷酸二酯酶 III 抑制剂奥普力农已被证实可改善心肌功能并增加脑血流量；因此，如果奥普力农对全脑缺血的直接神经保护作用与西洛他唑相当，那么奥普力农可能对心脏骤停后的脑复苏有用。我们在体内和体外检查了奥普力农是否直接保护神经元细胞免受全脑缺血的影响。
在由 4 血管闭塞引起的 10 分钟全脑缺血大鼠模型中，在缺血前 40 分钟内输注 0.3、3 或 30μg·kg-1·min-1奥普力农或生理盐水（每组 6 只）。再灌注 3 天后计数海马 CA1 神经元细胞的数量，并通过再灌注 15 分钟后获得的标本的 Western 印迹分析检查环磷酸腺苷 3'5'-单磷酸反应元件结合蛋白的磷酸化。在体外，将培养的大脑神经元暴露于 4 小时缺氧和葡萄糖剥夺，然后在没有或存在奥普力农（10-11-10-5mol·L-1）的情况下恢复 24 小时。使用 Cell Counting Kit-8（Dojindo Molecular Technologies，Gaithersburg，MD）测量细胞活力。
在全脑缺血大鼠模型中，在 30μg·kg-1·min-1奥普力农处理组（49.9±9.2）下显微镜视野下计数的存活 CA1 神经元数量明显高于生理盐水输注对照组（7.2±3.4），奥普力农治疗增加了环磷酸腺苷 3'5'-单磷酸反应元件结合蛋白的磷酸化。在存在奥普力农的情况下培养的神经元细胞的存活分数也明显高于不存在奥普力农的情况下培养的细胞，呈剂量依赖性。
我们的研究首次成功证明，奥普力农对体外和体内神经元细胞具有保护作用，特别是对全脑缺血。这些结果表明，奥普力农可能对全脑缺血患者的治疗有用。
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