Arruda Denise C, D'Alexandri Fabio Luiz, Katzin Alejandro M, Uliana Silvia R B
Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Professor Lineu Prestes, 1374, CEP 05508-900, São Paulo, SP, Brazil.
Antimicrob Agents Chemother. 2005 May;49(5):1679-87. doi: 10.1128/AAC.49.5.1679-1687.2005.
The activity of nerolidol, a sesquiterpene used as a food-flavoring agent and currently under testing as a skin penetration enhancer for the transdermal delivery of therapeutic drugs, was evaluated against Leishmania species. Nerolidol inhibited the growth of Leishmania amazonensis, L. braziliensis, and L. chagasi promastigotes and L. amazonensis amastigotes with in vitro 50% inhibitory concentrations of 85, 74, 75, and 67 microM, respectively. The treatment of L. amazonensis-infected macrophages with 100 microM nerolidol resulted in 95% reduction in infection rates. Inhibition of isoprenoid biosynthesis, as shown by reduced incorporation of [2-(14)C]mevalonic acid (MVA) or [1-(14)C]acetic acid precursors into dolichol, ergosterol, and ubiquinone, was observed in nerolidol-treated promastigotes. This drug effect can be attributed to the blockage of an early step in the mevalonate pathway, since incorporation of the precursor [1(n)-(3)H]farnesyl pyrophosphate in polyisoprenoids is not inhibited by nerolidol. L. amazonensis-infected BALB/c mice were treated with intraperitoneal doses of 100 mg/kg/day for 12 days or topically with 5 or 10% ointments for 4 weeks. Significant reduction of lesion sizes in nerolidol treated mice was observed for both treatment routes. However, long-term follow up indicated that the disease was not cured in this highly susceptible animal model. Nonetheless, the in vitro activity of nerolidol against these parasites may prove a useful tool for the development of new drugs for the treatment of leishmaniasis. In addition, biosynthesis of dolichols with 11 and 12 isoprene units was identified in Leishmania, as described for other trypanosomatids and Apicomplexa.
橙花叔醇是一种倍半萜，用作食品调味剂，目前正在作为治疗药物经皮递送的皮肤渗透促进剂进行测试。对其针对利什曼原虫属物种的活性进行了评估。橙花叔醇抑制亚马逊利什曼原虫、巴西利什曼原虫、恰加斯利什曼原虫前鞭毛体以及亚马逊利什曼原虫无鞭毛体的生长，其体外50%抑制浓度分别为85、74、75和67微摩尔。用100微摩尔橙花叔醇处理感染亚马逊利什曼原虫的巨噬细胞，感染率降低了95%。在经橙花叔醇处理的前鞭毛体中观察到类异戊二烯生物合成受到抑制，表现为[2-(14)C]甲羟戊酸（MVA）或[1-(14)C]乙酸前体掺入多萜醇、麦角甾醇和泛醌的量减少。这种药物作用可归因于甲羟戊酸途径早期步骤的阻断，因为橙花叔醇不抑制前体[1(n)-(3)H]法尼基焦磷酸掺入多聚异戊二烯。用腹腔注射剂量为100毫克/千克/天的橙花叔醇处理感染亚马逊利什曼原虫的BALB/c小鼠12天，或用5%或10%的软膏局部处理4周。两种处理途径均观察到经橙花叔醇处理的小鼠病变大小显著减小。然而，长期随访表明，在这种高度易感的动物模型中疾病并未治愈。尽管如此，橙花叔醇对这些寄生虫的体外活性可能证明是开发治疗利什曼病新药的有用工具。此外，如对其他锥虫和顶复门生物所描述的那样，在利什曼原虫中鉴定出了具有11和12个异戊二烯单元的多萜醇的生物合成。
