Schistosoma mansoni: Antischistosomal activity of the four optical isomers and the two racemates of mefloquine on schistosomula and adult worms in vitro and in vivo
Schistosoma mansoni: Antischistosomal activity of the four optical isomers and the two racemates of mefloquine on schistosomula and adult worms in vitro and in vivo
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DOI：
10.1016/j.exppara.2010.08.011
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发表时间：
2011-01-01
影响因子：
2.1
通讯作者：
Keiser, Jennifer
中科院分区：
文献类型：
--
作者：
Manneck, Theresia;Braissant, Olivier;Keiser, Jennifer
最近的研究表明，甲氟喹 (MQ) 具有有趣的抗血吸虫特性。我们在体外和在携带成年曼氏血吸虫的小鼠中检测了 MQ 的赤型和苏型异构体以及外消旋体对新转化的童虫 (NTS) 和曼氏血吸虫成虫的抗血吸虫活性。通过微量热法、扫描电子显微镜和表型评估监测存在和不存在血红素的体外效应。将NTS与浓度为3μg/ml及以上的赤型衍生物一起孵育会导致抽搐、颗粒化、热流降低和死亡，而与苏型衍生物一起孵育的NTS仅在高浓度（100μg/ml）时才会受到影响。当成年血吸虫暴露于10μg/ml的赤族化合物时，观察到广泛的皮膜改变、代谢活性、活力和死亡的降低。使用10μg/ml的苏式衍生物观察到中度的皮膜和活力变化，但产热率降低。在存在血红素的情况下，所有 MQ 衍生物均在体外对曼氏血吸虫成虫表现出明显的抗血吸虫特性。在体内，MQ 衍生物实现了统计显着的总蠕虫负担和雌性蠕虫负担减少，范围在 65.4% 至 100% 之间。在用赤型和苏型外消旋体处理后，观察到最高的总蠕虫负荷降低分别为 93.4% 和 90.2%。总之，MQ 的光学异构体和外消旋体仅表现出中等的立体选择性，特别是在体内。我们的结果可能会增强我们对 MQ 衍生物对血吸虫的作用机制和治疗概况的理解。 (C) 2010 Elsevier Inc. 保留所有权利。
Recent studies have shown that mefloquine (MQ) reveals interesting antischistosomal properties. We examined the antischistosomal activities of the erythro and threo isomers and racemates of MQ on newly transformed schistosomula (NTS) and adult Schistosoma mansoni in vitro and in mice harbouring adult S. mansoni. The in vitro effects in the presence and absence of haemin were monitored by means of microcalorimetry, scanning electron microscopy and phenotypic evaluation. Incubation of NTS with the erythro derivatives at concentrations of 3 mu g/ml and above resulted in convulsions, granularity, decrease in heat flow, and death while NTS incubated with the threo derivatives were only affected at high concentrations (100 mu g/ml). Extensive tegumental alterations, decrease in metabolic activity, viability, and death were observed when adult schistosomes had been exposed to 10 mu g/ml of the erythro compounds. Moderate tegumental and viability changes but reduced heat production rates were observed with the threo derivatives at 10 mu g/ml. In the presence of haemin, all MQ derivatives showed pronounced antischistosomal properties against adult S. mansoni in vitro. In vivo, MQ derivatives achieved statistically significant total and female worm burden reductions ranging between 65.4% and 100%. The highest total worm burden reductions of 93.4% and 90.2% were observed following treatment with the erythro and threo racemates, respectively. In conclusion, the optical isomers and racemates of MQ show only moderate stereoselectivity, in particular in vivo. Our results may enhance our understanding of the mechanism of action and therapeutic profile of MQ derivates on schistosomes. (C) 2010 Elsevier Inc. All rights reserved.