Clonidine transport at the mouse blood-brain barrier by a new H+ antiporter that interacts with addictive drugs
Clonidine transport at the mouse blood-brain barrier by a new H+ antiporter that interacts with addictive drugs
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DOI：
10.1038/jcbfm.2009.54
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发表时间：
2009-07-01
影响因子：
6.3
通讯作者：
Cisternino, Salvatore
中科院分区：
文献类型：
--
作者：
Andre, Pascal;Debray, Marcel;Cisternino, Salvatore
确定药物转运蛋白及其在体内的意义将有助于解释为什么一些中枢神经系统（CNS）药物穿过血脑屏障（BBB）并到达脑实质。我们的特点是运输的药物可乐定在腔血脑屏障在原位小鼠脑灌注。可乐定内流是饱和的，其次是米氏动力学（Km = 0.62 mmol/ L，V-max = 1.76 nmol/sec/g，pH 7.40），是不敏感的钠和跨膜电位。在体内操作的细胞内和/或细胞外的pH值和反式刺激表明，可乐定的质子和可乐定梯度调节的H+-偶联的反向转运蛋白运输，苯海拉明也是一个底物。有机阳离子转运蛋白（Oct 1 -3），P-gp和Bcrp没有改变敲除小鼠血脑屏障中可乐定的转运。二级或三级胺CNS化合物，如羟考酮、吗啡、二乙酰吗啡、亚甲二氧基苯丙胺（MDMA）、可卡因和尼古丁抑制可乐定转运。然而，与胆碱，Mate，Octn和Pmat转运蛋白相互作用的阳离子化合物没有。这表明可乐定是通过一种新的H+偶联可逆反向转运蛋白在小鼠血脑屏障中转运的。脑血流与代谢杂志（2009）29，1293- 1304; doi：10.1038/jcbfm.2009.54; 2009年5月20日在线发表
Identifying drug transporters and their in vivo significance will help to explain why some central nervous system (CNS) drugs cross the blood-brain barrier (BBB) and reach the brain parenchyma. We characterized the transport of the drug clonidine at the luminal BBB by in situ mouse brain perfusion. Clonidine influx was saturable, followed by Michaelis-Menten kinetics (K-m = 0.62 mmol/ L, V-max = 1.76 nmol/sec per g at pH 7.40), and was insensitive to both sodium and trans-membrane potential. In vivo manipulation of intracellular and/or extracellular pH and trans-stimulation showed that clonidine was transported by an H+-coupled antiporter regulated by both proton and clonidine gradients, and that diphenhydramine was also a substrate. Organic cation transporters (Oct1-3), P-gp, and Bcrp did not alter clonidine transport at the BBB in knockout mice. Secondary or tertiary amine CNS compounds such as oxycodone, morphine, diacetylmorphine, methylenedioxyamphetamine (MDMA), cocaine, and nicotine inhibited clonidine transport. However, cationic compounds that interact with choline, Mate, Octn, and Pmat transporters did not. This suggests that clonidine is transported at the luminal mouse BBB by a new H+-coupled reversible antiporter. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1293- 1304; doi: 10.1038/jcbfm.2009.54; published online 20 May 2009