Araújo Iasmin Aparecida Cunha, de Paula Renata Cristina, Alves Ceres Luciana, Faria Karen Ferraz, Oliveira Marco Miguel de, Mendes Gabriela Gonçalves, Dias Eliane Martins Ferreira Abdias, Ribeiro Raul Rio, Oliveira Alaíde Braga de, Silva Sydnei Magno da
Laboratory of Bioassays in Leishmania, Institute of Biomedical Sciences, Federal University of Uberlandia, Para Avenue, 1720 - Umuarama Campus, 38400-920, Uberlandia, Minas Gerais State, Brazil.
Laboratory of Phytochemistry, Department of Pharmaceutical Products, Federal University of Minas Gerais, Antonio Carlos Avenue, 6627 - Pampulha Campus, 31270-901, Belo Horizonte, Minas Gerais State, Brazil.
Exp Parasitol. 2019 Apr;199:67-73. doi: 10.1016/j.exppara.2019.02.013. Epub 2019 Feb 21.
Leishmaniasis is one of the most important neglected diseases worldwide. It is a life-threatening disease and causes significant morbidity, long-term disability, and early death. Treatment involves disease control or use of intervention measures, although the currently used drugs require long-lasting therapy, and display toxicity and reduced efficacy. The use of natural products isolated from plants, such as lapachol, an abundant naphthoquinone naturally occurring in South American Handroanthus species (Tabebuia, Bignoniaceae), is a promising option for the treatment of leishmaniasis. In this study, we investigated the leishmanicidal activity of lapachol in vitro and in vivo against Leishmania infantum and L. amazonensis, causative agents of visceral and cutaneous leishmaniasis, respectively. Low cytotoxicity in HepG2 cells (3405.8 ± 261.33 μM), good anti-Leishmania activity, and favorable selectivity indexes (SI) against promastigotes of both L. amazonensis (IC = 79.84 ± 9.10 μM, SI = 42.65) and L. infantum (IC = 135.79 ± 33.04 μM, SI = 25.08) were observed. Furthermore, anti-Leishmania activity assays performed on intracellular amastigotes showed good activity for lapachol (IC = 191.95 μM for L. amazonensis and 171.26 μM for L. infantum). Flow cytometric analysis demonstrated that the cytotoxic effect of lapachol in Leishmania promastigotes was caused by apoptosis-like death. Interestingly, the in vitro leishmanicidal effect of lapachol was confirmed in vivo in murine models of visceral and cutaneous leishmaniasis, as lapachol (25 mg/kg oral route for 24 h over 10 days) was able to significantly reduce the parasitic load in skin lesions, liver, and spleen, similar to amphotericin B, the reference drug. These results reinforce the therapeutic potential of lapachol, which warrants further investigations as an anti-leishmaniasis therapeutic.
利什曼病是全球最重要的被忽视疾病之一。它是一种危及生命的疾病，会导致严重发病、长期残疾和过早死亡。治疗方法包括疾病控制或采取干预措施，尽管目前使用的药物需要长期治疗，且具有毒性且疗效降低。使用从植物中分离出的天然产物，如拉帕醇，一种在南美洲的掌叶树属植物（紫葳科蓝花楹属）中大量天然存在的萘醌，是治疗利什曼病的一个有前景的选择。在本研究中，我们调查了拉帕醇在体外和体内对婴儿利什曼原虫和亚马逊利什曼原虫的杀利什曼活性，它们分别是内脏利什曼病和皮肤利什曼病的病原体。在HepG2细胞中观察到低细胞毒性（3405.8±261.33μM）、良好的抗利什曼活性以及对亚马逊利什曼原虫（IC = 79.84±9.10μM，SI = 42.65）和婴儿利什曼原虫（IC = 135.79±33.04μM，SI = 25.08）前鞭毛体的良好选择性指数（SI）。此外，对细胞内无鞭毛体进行的抗利什曼活性测定显示拉帕醇具有良好活性（对亚马逊利什曼原虫IC = 191.95μM，对婴儿利什曼原虫IC = 171.26μM）。流式细胞术分析表明，拉帕醇对利什曼原虫前鞭毛体的细胞毒性作用是由凋亡样死亡引起的。有趣的是，拉帕醇的体外杀利什曼作用在体内的内脏和皮肤利什曼病小鼠模型中得到证实，因为拉帕醇（25mg/kg口服给药，持续24小时，共10天）能够显著降低皮肤病变、肝脏和脾脏中的寄生虫负荷，与参考药物两性霉素B相似。这些结果强化了拉帕醇的治疗潜力，其作为抗利什曼病治疗药物值得进一步研究。
