Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.
Instituto de Microbiologia Paulo de Góes, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.
Sci Rep. 2020 Jun 30;10(1):10642. doi: 10.1038/s41598-020-67324-8.
Chagas disease is an important disease affecting millions of patients in the New World and is caused by a protozoan transmitted by haematophagous kissing bugs. It can be treated with drugs during the early acute phase; however, effective therapy against the chronic form of Chagas disease has yet to be discovered and developed. We herein tested the activity of solenopsin alkaloids extracted from two species of fire ants against the protozoan parasite Trypanosoma cruzi, the aetiologic agent of Chagas disease. Although IC determinations showed that solenopsins are more toxic to the parasite than benznidazole, the drug of choice for Chagas disease treatment, the ant alkaloids presented a lower selectivity index. As a result of exposure to the alkaloids, the parasites became swollen and rounded in shape, with hypertrophied contractile vacuoles and intense cytoplasmic vacuolization, possibly resulting in osmotic stress; no accumulation of multiple kinetoplasts and/or nuclei was detected. Overexpressing phosphatidylinositol 3-kinase-an enzyme essential for osmoregulation that is a known target of solenopsins in mammalian cells-did not prevent swelling and vacuolization, nor did it counteract the toxic effects of alkaloids on the parasites. Additional experimental results suggested that solenopsins induced a type of autophagic and programmed cell death in T. cruzi. Solenopsins also reduced the intracellular proliferation of T. cruzi amastigotes in infected macrophages in a concentration-dependent manner and demonstrated activity against Trypanosoma brucei rhodesiense bloodstream forms, which is another important aetiological kinetoplastid parasite. The results suggest the potential of solenopsins as novel natural drugs against neglected parasitic diseases caused by kinetoplastids.
恰加斯病是一种重要的疾病，影响着新世界数百万患者，由吸血接吻虫传播的原生动物引起。在早期急性阶段可以用药物治疗；然而，尚未发现和开发出针对恰加斯病慢性形式的有效疗法。我们在此测试了从两种火蚁中提取的 solenopsin 生物碱对原生动物寄生虫克氏锥虫的活性，克氏锥虫是恰加斯病的病原体。虽然 IC 测定表明 solenopsins 比治疗恰加斯病的首选药物苯并咪唑对寄生虫更有毒性，但抗蚁生物碱的选择性指数较低。由于暴露于生物碱，寄生虫变得肿胀和圆形，收缩泡肥大，细胞质空泡化强烈，可能导致渗透胁迫；未检测到多个动基体和/或核的积累。过表达磷脂酰肌醇 3-激酶——一种对渗透调节至关重要的酶，也是哺乳动物细胞中 solenopsins 的已知靶点——不能防止肿胀和空泡化，也不能抵消生物碱对寄生虫的毒性作用。额外的实验结果表明， solenopsins 在 T. cruzi 中诱导了一种自噬和程序性细胞死亡。 solenopsins 还以浓度依赖的方式减少了感染巨噬细胞中 T. cruzi 无鞭毛体的细胞内增殖，并对布氏锥虫罗得西亚血流形式表现出活性，这是另一种重要的寄生虫动基体寄生虫。结果表明 solenopsins 有潜力成为针对由动基体寄生虫引起的被忽视的寄生虫病的新型天然药物。
