Increasing oxime efficacy by blood-brain barrier modulation
Increasing oxime efficacy by blood-brain barrier modulation
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DOI：
10.1016/j.toxlet.2011.05.231
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发表时间：
2011-09-25
影响因子：
3.5
通讯作者：
van Helden, Herman P. M.
中科院分区：
文献类型：
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作者：
Joosen, Marloes J. A.;van der Schans, Marcel J.;van Helden, Herman P. M.
目前治疗神经毒剂中毒的一个缺点是，肟很难穿透血脑屏障（BBB），而神经毒剂很容易穿透。因此，增加大脑中肟的浓度将提供一种改善医疗对策的有吸引力的方法。对有限渗透的一种解释可能是，氧肟是血脑屏障中活性p -糖蛋白（Pgp）外排转运蛋白的底物。采用定量脑微透析的方法，研究了静脉注射非竞争性特异性pgp抑制剂tariquar对大鼠血液和脑中HI-6水平的影响。在HI-6给药后的第一个小时内，tariquar似乎使大脑中的HI-6水平提高了约2倍，而血浆中HI-6水平在治疗组之间没有差异。随后在大鼠中进行的概念验证研究表明，除HI-6和阿托品外，用塔奎达进行预处理，几乎可以完全预防索曼诱发的癫痫发作和惊厥。此外，它们大脑中的乙酰胆碱酯酶活性是对照大鼠的两倍。这些大鼠实验结果表明，像tariquar这样本身无毒的药物对血脑屏障的调节在提高肟类药物的疗效方面具有重要价值。2011爱思唯尔爱尔兰有限公司版权所有。
One of the shortcomings of current treatment of nerve agent poisoning is that oximes hardly penetrate the blood-brain barrier (BBB), whereas nerve agents easily do. Increasing the concentration of oximes in the brain, would therefore provide an attractive approach to improve medical countermeasures. An explanation for limited penetration might be that oximes are substrates for the active P-glycoprotein (Pgp) efflux transporter located in the BBB.Using quantitative brain microdialysis in rats, the effect of i.v. injected tariquidar, a non-competitive, specific Pgp-inhibitor, on HI-6 levels in blood and brain was investigated. It appeared that tariquidar enhanced HI-6 levels in the brain approximately 2-fold during the first hour after HI-6 administration, whereas plasma levels did not differ between the treatment groups. A subsequent proof-of-concept study in rats showed that soman-induced seizures and convulsions were prevented almost completely when they were, in addition to HI-6 and atropine, pretreated with tariquidar. Moreover, twice as much AChE activity was present in their brains as compared to control rats.These results in rats indicate that modulation of the BBB by a drug like tariquidar, which is non-toxic by itself, is of great value in enhancing the efficacy of oximes. (C) 2011 Elsevier Ireland Ltd. All rights reserved.