Duarte Mariana Costa, Lage Letícia Martins Dos Reis, Lage Daniela Pagliara, Martins Vívian Tamietti, Carvalho Ana Maria Ravena Severino, Roatt Bruno Mendes, Menezes-Souza Daniel, Tavares Carlos Alberto Pereira, Alves Ricardo José, Barichello José Mário, Coelho Eduardo Antonio Ferraz
Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil; Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil.
Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil.
Parasitol Int. 2016 Dec;65(6 Pt A):728-736. doi: 10.1016/j.parint.2016.07.005. Epub 2016 Jul 15.
New therapeutics are urgently needed to treat visceral leishmaniasis (VL). Due to the fact that drug discovery is a long and expensive process, the development of delivery systems to carry old and toxic drugs could be considered, as well as the evaluation of new molecules that have already shown to present biological activity. In this context, the present study evaluated the in vitro and in vivo antileishmanial activity of an 8-hydroxyquinoline (8-HQN)-containing polymeric micelle (8-HQN/M) system against Leishmania infantum, the main causative agent of VL in the Americas. The experimental strategy used was based on the evaluation of the parasite load by a limiting-dilution technique in the spleen, liver, bone marrow and draining lymph nodes of the infected and treated animals, as well as by a quantitative PCR (qPCR) technique to also assess the splenic parasite load. The immune response developed was evaluated by the production of IFN-γ, IL-4, IL-10, IL-12 and GM-CSF cytokines, as well as by antileishmanial nitrite dosage and antibodies production. Hepatic and renal enzymes were also investigated to verify cellular injury as a result of treatments toxicity. In the results, 8-HQN/M-treated mice, when compared to the other groups: saline, free amphotericin B (AmpB, as a drug control), 8-HQN and B-8-HQN/M (as a micelle control) showed more significant reductions in their parasite burden in all evaluated organs. These animals also showed an antileishmanial Th1 immunity, which was represented by high levels of IFN-γ, IL-12, GM-CSF and nitrite, associated with a low production of IL-4 and IL-10 and anti-Leishmania IgG1 isotype antibodies. In addition, any hepatic or renal damage was found in these treated animals. In conclusion, 8-HQN/M was effective in treating L. infantum-infected BALB/c mice, and can be considered alone, or combined with other drugs, as an alternative treatment for VL.
治疗内脏利什曼病（VL）迫切需要新的治疗方法。由于药物研发是一个漫长且昂贵的过程，因此可以考虑开发用于递送旧的有毒药物的给药系统，以及评估已显示具有生物活性的新分子。在此背景下，本研究评估了一种含8-羟基喹啉（8-HQN）的聚合物胶束（8-HQN/M）系统对婴儿利什曼原虫的体外和体内抗利什曼活性，婴儿利什曼原虫是美洲VL的主要病原体。所采用的实验策略基于通过有限稀释技术评估感染和治疗动物的脾脏、肝脏、骨髓和引流淋巴结中的寄生虫负荷，以及通过定量PCR（qPCR）技术评估脾脏中的寄生虫负荷。通过检测IFN-γ、IL-4、IL-10、IL-12和GM-CSF细胞因子的产生、抗利什曼亚硝酸盐剂量以及抗体产生来评估所产生的免疫反应。还研究了肝酶和肾酶以验证治疗毒性导致的细胞损伤。结果显示，与其他组（生理盐水、游离两性霉素B（AmpB，作为药物对照）、8-HQN和B-8-HQN/M（作为胶束对照））相比，接受8-HQN/M治疗的小鼠在所有评估器官中的寄生虫负担均有更显著降低。这些动物还表现出抗利什曼Th1免疫，表现为高水平的IFN-γ、IL-12、GM-CSF和亚硝酸盐，同时IL-4和IL-10以及抗利什曼IgG1同种型抗体的产生较低。此外，在这些接受治疗的动物中未发现任何肝损伤或肾损伤。总之，8-HQN/M可有效治疗感染婴儿利什曼原虫的BALB/c小鼠，可单独使用或与其他药物联合使用，作为VL的替代治疗方法。
