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Study on reversal of chloroquine resistance in malaria parasites by Ca^<2+> antagonists

Ca^2拮抗剂逆转疟原虫氯喹耐药性的研究

基本信息

批准号：
02807044
负责人：
TANABE Kazuyuki
金额：
$ 1.28万
依托单位：
Osaka Institute of Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02807044/
关键词：
Malaria Parasite Plasmodium Chloroquine Ca^<2+> Antagonists Calmodulin Inhibitors Antidepressants Drug Resistance Pyrimethamine

项目摘要

1. Preliminary study revealed that several Ca^<2+> antagonists reversed chloroquine (CQ) resistance in mice infected with CQ-resistant Plasmodium chabaudi. In addition to Ca^<2+> antagonists, calmodulin inhibitors, trifluoperazine and chlorpromazine, and tricyclic antidepressants, desipramine and imipramine, reversed CQ-resistance in a dose-dependent manner. These drugs also increased the susceptibility to CQ in CQsensitive P. chabaudi.2. Ca^<2+> antagonists, calmodulin inhibitors and tricyclic antidepressants used in this study did not reverse pyrimethamine resistance in miceinfected with pyrimethamine-resistant P-. chabaudi.3. Measurements of CQ levels in P. chabaudi by high performance liquid" chromatography demonstrated that CQ accumulated in CQ-sensitive parasites much greater than in CQ-resistant parasites. Time-dependent increase in the accumulation of CQ was less pronounced in CQ-resistant parasites.4. Transmission electron microscopy elucidated that CQ induced a variety of morphological changes in CQsensitive P. chabaudi : swelling of the food vacuoles and clustering of malaria pigment in the food vacuole at 2.5hr after injection of CQ and at 24 and 481ir disappearance of endoplasmic reticulum, aggregation of ribosomes and appearance of electron-dense granules in the nucleus. These changes were not observed in CQ-resistant P. chabaudi. However, verapamil induced ultrastructural changes very similar to those observed in CQ-sensitive parasites.These results indicate that Ca^<2+> antagonists reverse CQ resistance by inducing the accumulation of CQ in resistant P. chabaudi.

1. 初步研究表明，几种Ca^<2+>拮抗剂逆转了感染CQ抗性chabaudi疟原虫小鼠对氯喹（CQ）的抗性。除了Ca^<2+>拮抗剂，钙调素抑制剂，三氟哌嗪和氯丙嗪，三环抗抑郁药，地西帕明和丙咪嗪，以剂量依赖性的方式逆转cq耐药。这些药物也增加了CQ敏感的chabhadip对CQ的易感性。本研究中使用的Ca^<2+>拮抗剂、钙调素抑制剂和三环抗抑郁药不能逆转感染了乙胺耐药P-的小鼠的乙胺耐药。chabaudi.3。高效液相色谱法测定chabaudi中CQ的含量，结果表明CQ在CQ敏感寄生虫中的积累量远大于CQ抗性寄生虫。在CQ抗性寄生虫中，CQ积累的时间依赖性增加不太明显。透射电镜观察发现，CQ可引起CQ敏感的沙斑蝶多种形态变化：注射CQ后2.5h食物液泡肿胀，食物液泡内疟疾色素聚集，24和481h内质网消失，核糖体聚集，细胞核内出现电子致密颗粒。这些变化在抗cq的白僵菌中没有观察到。然而，维拉帕米诱导的超微结构变化与cq敏感寄生虫的超微结构变化非常相似。这些结果表明，Ca^<2+>拮抗剂通过诱导CQ积累逆转CQ抗性。