Schistosomicidal and anti-fecundity effects of oral treatment of synthetic endoperoxide compound N-89
Schistosomicidal and anti-fecundity effects of oral treatment of synthetic endoperoxide compound N-89
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合成内过氧化物化合物 N-89 口服治疗的杀血吸虫和抗生育作用
DOI：
10.1016/j.parint.2011.02.007
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发表时间：
2011
影响因子：
1.9
通讯作者：
Ohta N
中科院分区：
文献类型：
--
作者：
Taniguchi T;Kumagai T;Shimogawara R;Ichinose S;Hiramoto A;Sato A;Morita M;Nojima M;Kim HS;Wataya Y;Ohta N
1,2,6,7-四氧阿斯匹罗[7.11]壬烷（N-89）是一种化学合成的抗疟原虫有效化合物。在体外和体内均观察到N-89具有较强的抗血吸虫活性。在实验感染曼氏血吸虫的小鼠模型中，在感染后2周，口服剂量为300 mg/kg的N-89可显著减少小鼠的蠕虫负荷（63%）。体外实验证实N-89有较强的杀幼虫作用；schistosomula ofS。N-89杀灭曼森，EC50为16 nM。相比之下，在体内感染后5周给予N-89时，没有观察到蠕虫负荷的显著减少。然而，N-89处理显著抑制了该时间点的产蛋量。显微镜观察，与对照组相比，n -89处理的雌虫肠道似乎是空的，平均体长明显短于对照组。由于N-89处理可能导致寄生虫营养受损，因此比较了N-89处理和未处理寄生虫的血色素蛋白定量。我们发现，与对照组相比，N-89处理的疟原虫色素含量显著降低（P< 0.001）。用扫描电镜和透射电镜观察成虫表面，未见明显变化。综上所述，这些观察结果表明N-89具有很强的抗血吸虫作用，可能是通过一种独特的药物功效模式。由于N-89对哺乳动物宿主的毒性较低，因此可能是一种抗血吸虫病的候选药物。
1,2,6,7-Tetraoxaspiro[7.11]nonadecane (N-89) is a chemically synthesized compound with good efficacy against malaria parasites. We observed strong anti-schistosomal activities of N-89 bothin vitroandin vivo. In a murine model with experimental infection of Schistosoma mansoni, orally administered N-89 at the dose of 300 mg/kg resulted in a significant reduction in worm burden (63%) when mice were treated at 2-weeks postinfection. Strong larvicidal effects of N-89 were confirmedin vitro; schistosomula ofS. mansoniwere killed by N-89 at an EC50 of 16 nM. In contrast, no significant reduction in worm burden was observed when N-89 was administered at 5 weeks postinfectionin vivo. However, egg production was markedly suppressed by N-89 treatment at that time point. On microscopic observation, the intestine of N-89-treated female worms seemed to be empty compared with the control group, and the mean body length was significantly shorter than that of controls. Nutritional impairment in the parasite due to N-89 treatment was possible, and therefore quantification of hemozoin was compared between parasites with or without N-89 treatment. We found that the hemozoin content was significantly reduced in N-89 treated parasites compared with controls (P< 0.001). The surface of adult worms was observed by scanning and transmission electron microscopy, but there were no apparent changes. Taken together, these observations suggested that N-89 has strong antischistosomal effects, probably through a unique mode of drug efficacy. As N-89 is less toxic to mammalian host animals, it is a possible drug candidate against schistosomiasis.