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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：诱导虫族代谢在啮齿动物脑渗透和肺炎症慢性模型中的脑渗透和影响的后果

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摘要

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：通过阻断Na-k-Cl Cotroangerporter（NKCC）来抑制神经元NKCC1的利尿剂硼铵，特别是当NKCC1表达在脑病如癫痫患者中异常增加时。然而，由于对其正丁基旁路的广泛氧化，沸腾渗透到大脑中，并且在啮齿动物中，迅速消除，从而降低啮齿动物实验的平移价值。先前据报道，通过哌隆丁丁氧化物（PBO）抑制氧化硼氧化丁氧化物（PBO）以增加大鼠硼铵的半衰期和利尿剂活性。在这里，我们研究了POGO的抑制硼酸酯代谢的抑制还会增加大鼠肺酸酐的大脑水平，以及这是否改变了癫痫的点燃模型中的药物动力学作用。此外，我们研究了PBO在小鼠中的作用。小鼠比大鼠迅速消除硼铀（消除半衰期47分钟与13分钟）。用PBO预处理将小鼠的半衰期增加到先前在人类中确定的平均值（70分钟），并显着升高了脐酐的脑水平。在大鼠中，PBO通过PBO血浆和大脑水平的增加显着显着显着。 PBO显着提高了大鼠浓铀的利尿剂活性，并且在小鼠中较小有效。在癫痫小鼠中，硼铵（用PbO）没有抑制自发的癫痫发作。在大鼠点燃模型中，硼乙胺（有或没有PBO）对完全点燃的癫痫发作并未发挥抗惊厥作用，但剂量依赖性改变了新鲜的新药。这些数据表明，PBO提供了一种简单的方法，以提高啮齿动物实验的平移性质与硼铀，特别是在使用小鼠时。

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  • 作者

    T?pferM.; T?llnerK.; BrandtC.; TweleF.; Br?erS.; L?scherW.;

  • 作者单位

    Department of Pharmacology Toxicology and Pharmacy University of Veterinary Medicine Bünteweg 17;

    Department of Pharmacology Toxicology and Pharmacy University of Veterinary Medicine Bünteweg 17;

    Department of Pharmacology Toxicology and Pharmacy University of Veterinary Medicine Bünteweg 17;

    Department of Pharmacology Toxicology and Pharmacy University of Veterinary Medicine Bünteweg 17;

    Department of Pharmacology Toxicology and Pharmacy University of Veterinary Medicine Bünteweg 17;

    Department of Pharmacology Toxicology and Pharmacy University of Veterinary Medicine Bünteweg 17;

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  • 正文语种 eng
  • 中图分类 神经病学与精神病学;
  • 关键词

    Blood-brain barrier; Diuresis; Epilepsy; Kindling; Piperonyl butoxide; Seizures;

    机译：血脑屏障;利尿症;癫痫;点燃;哌隆丁基;癫痫发作;

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