Chierrito Talita P C, Aguiar Anna C C, de Andrade Isabel M, Ceravolo Isabela P, Gonçalves Regina A C, de Oliveira Arildo J B, Krettli Antoniana U
Faculdade de Medicina, Programa de Pós-Graduação em Medicina Molecular, Universidade Federal de Minas Gerais, Prof, Alfredo Balena, 190, 30130-100 Belo Horizonte, MG, Brazil.
Malar J. 2014 Apr 14;13:142. doi: 10.1186/1475-2875-13-142.
Several species of Aspidosperma (Apocynaceae) are used as treatments for human diseases in the tropics. Aspidosperma olivaceum, which is used to treat fevers in some regions of Brazil, contains the monoterpenoid indole alkaloids (MIAs) aspidoscarpine, uleine, apparicine, and N-methyl-tetrahydrolivacine. Using bio-guided fractionation and cytotoxicity testing in a human hepatoma cell line, several plant fractions and compounds purified from the bark and leaves of the plant were characterized for specific therapeutic activity (and selectivity index, SI) in vitro against the blood forms of Plasmodium falciparum.
The activity of A. olivaceum extracts, fractions, and isolated compounds was evaluated against chloroquine (CQ)-resistant P. falciparum blood parasites by in vitro testing with radiolabelled [3H]-hypoxanthine and a monoclonal anti-histidine-rich protein (HRPII) antibody. The cytotoxicity of these fractions and compounds was evaluated in a human hepatoma cell line using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, and the SI was calculated as the ratio between the toxicity and activity. Two leaf fractions were tested in mice with Plasmodium berghei.
All six fractions from the bark and leaf extracts were active in vitro at low doses (IC50 < 5.0 μg/mL) using the anti-HRPII test, and only two (the neutral and basic bark fractions) were toxic to a human cell line (HepG2). The most promising fractions were the crude leaf extract and its basic residue, which had SIs above 50. Among the four pure compounds evaluated, aspidoscarpine in the bark and leaf extracts showed the highest SI at 56; this compound, therefore, represents a possible anti-malarial drug that requires further study. The acidic leaf fraction administered by gavage to mice with blood-induced malaria was also active.
Using a bio-monitoring approach, it was possible to attribute the anti-P. falciparum activity of A. olivaceum to aspidoscarpine and, to a lesser extent, N-methyl-tetrahydrolivacine; other isolated MIA molecules were active but had lower SIs due to their higher toxicities. These results stood in contrast to previous work in which the anti-malarial activity of other Aspidosperma species was attributed to uleine.
几种阿氏马钱属植物（夹竹桃科）在热带地区被用于治疗人类疾病。在巴西的一些地区，用于治疗发烧的橄榄叶阿氏马钱含有单萜吲哚生物碱（MIAs），如阿氏马钱碱、乌来宁、阿帕里辛和N - 甲基 - 四氢利瓦辛。通过生物导向分级分离和在人肝癌细胞系中的细胞毒性测试，对从该植物树皮和叶子中纯化得到的几种植物提取物和化合物进行了体外针对恶性疟原虫血液阶段的特定治疗活性（以及选择性指数，SI）的表征。
通过用放射性标记的[3H] - 次黄嘌呤和单克隆抗富含组氨酸蛋白（HRPII）抗体进行体外测试，评估橄榄叶阿氏马钱提取物、馏分和分离化合物对氯喹（CQ）耐药的恶性疟原虫血液寄生虫的活性。使用3 - [4,5 - 二甲基噻唑 - 2 - 基] - 2,5 - 二苯基溴化四氮唑（MTT）测定法在人肝癌细胞系中评估这些馏分和化合物的细胞毒性，并将SI计算为毒性与活性之比。在感染伯氏疟原虫的小鼠中测试了两种叶提取物。
使用抗HRPII测试，树皮和叶提取物的所有六个馏分在低剂量（IC50 <5.0μg/mL）下体外均有活性，并且只有两个（树皮中性和碱性馏分）对人细胞系（HepG2）有毒性。最有前景的馏分是粗叶提取物及其碱性残留物，其SI高于50。在所评估的四种纯化合物中，树皮和叶提取物中的阿氏马钱碱的SI最高，为56；因此，该化合物代表一种可能需要进一步研究的抗疟药物。通过灌胃给予血液诱导型疟疾小鼠的酸性叶馏分也有活性。
采用生物监测方法，可以将橄榄叶阿氏马钱的抗恶性疟原虫活性归因于阿氏马钱碱，在较小程度上归因于N - 甲基 - 四氢利瓦辛；其他分离的MIA分子有活性，但由于毒性较高，SI较低。这些结果与之前将其他阿氏马钱属物种的抗疟活性归因于乌来宁的研究结果形成对比。
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