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首页> 外文期刊>The European Journal of Neuroscience >Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy
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Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy

机译：啮齿类动物中布美他尼代谢抑制对脑渗透的影响以及布美他尼在慢性癫痫模型中的作用

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The diuretic bumetanide, which acts by blocking the Na-K-Cl cotransporter (NKCC), is widely used to inhibit neuronal NKCC1, particularly when NKCC1 expression is abnormally increased in brain diseases such as epilepsy. However, bumetanide poorly penetrates into the brain and, in rodents, is rapidly eliminated because of extensive oxidation of its N-butyl sidechain, reducing the translational value of rodent experiments. Inhibition of oxidation by piperonyl butoxide (PBO) has previously been reported to increase the half-life and diuretic activity of bumetanide in rats. Here we studied whether inhibition of bumetanide metabolism by PBO also increases brain levels of bumetanide in rats, and whether this alters pharmacodynamic effects in the kindling model of epilepsy. Furthermore, we studied the effects of PBO in mice. Mice eliminated bumetanide less rapidly than rats (elimination half-life 47 min vs. 13 min). Pretreatment with PBO increased the half-life in mice to average values (70 min) previously determined in humans, and markedly elevated brain levels of bumetanide. In rats, the increase in plasma and brain levels of bumetanide by PBO was less marked than in mice. PBO significantly increased the diuretic activity of bumetanide in rats and, less effectively, in mice. In epileptic mice, bumetanide (with PBO) did not suppress spontaneous seizures. In the rat kindling model, bumetanide (with or without PBO) did not exert anticonvulsant effects on fully kindled seizures, but dose-dependently altered kindling development. These data indicate that PBO offers a simple means to enhance the translational properties of rodent experiments with bumetanide, particularly when using mice.
机译：利尿布美他尼通过阻断Na-K-Cl共转运蛋白（NKCC）发挥作用，被广泛用于抑制神经元NKCC1，尤其是在癫痫等脑部疾病中NKCC1表达异常增加时。但是，布美他尼难以渗透到大脑中，并且在啮齿动物中由于其N-丁基侧链的广泛氧化而被迅速消除，从而降低了啮齿动物实验的翻译价值。先前已经报道了通过胡椒基丁醚（PBO）抑制氧化作用可增加布美他尼在大鼠中的半衰期和利尿活性。在这里，我们研究了PBO对布美他尼代谢的抑制作用是否还会增加大鼠中布美他尼的大脑水平，以及这是否会改变癫痫点燃模型中的药效学作用。此外，我们研究了PBO在小鼠中的作用。小鼠消除布美他尼的速度不及大鼠快（消除半衰期分别为47分钟和13分钟）。用PBO预处理可将小鼠的半衰期延长至先前在人类中确定的平均值（70分钟），并显着提高布美他尼的脑水平。在大鼠中，PBO引起的布美他尼血浆和脑水平的增加没有小鼠明显。 PBO显着增加了布美他尼在大鼠中的利尿活性，但对小鼠却没有那么有效。在癫痫小鼠中，布美他尼（含PBO）不能抑制自发性癫痫发作。在大鼠点燃模型中，布美他尼（有或没有PBO）对完全点燃的癫痫发作均无惊厥作用，但剂量依赖性地改变了点燃发展。这些数据表明，PBO提供了一种简单的方法来增强布美他尼啮齿动物实验的翻译特性，尤其是在使用小鼠时。

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