Antileishmanial activity and ultrastructural alterations of Leishmania (L.) chagasi treated with the calcium channel blocker nimodipine.
In a search for novel antileishmanial drugs, we investigated the activity of the calcium channel blocker nimodipine against Leishmania spp. and explored the ultrastructural damages of parasites induced by nimodipine after a short period of incubation. Nimodipine was highly effective against promastigotes and intracellular amastigotes of Leishmania (L.) chagasi, with 50% inhibitory concentration values of 81.2 and 21.5 muM, respectively. Nimodipine was about fourfold more effective than the standard pentavalent antimony against amastigotes and showed a Selectivity Index of 4.4 considering its mammalian cells toxicity. Leishmania (L.) amazonensis and Leishmania (L.) major promastigotes were also susceptible to nimodipine in a range concentration between 31 and 128 muM. Ultrastructural studies of L. (L.) chagasi revealed intense mitochondria damage and plasma membrane blebbing, resulting in a leishmanicidal effect as demonstrated by the lack of mitochondrial oxidative metabolism. The amastigote-killing effect suggests other mechanism than macrophage activation, as no upregulation of nitric oxide was seen. This calcium channel blocker is an effective in vitro antileishmanial compound and if adequately studied could be used as a novel drug candidate or as a novel drug lead compound for drug design studies against leishmaniasis.
Laboratório de Toxinologia Aplicada, Departamento de Parasitologia, Instituto Adolfo Lutz, Av. Dr. Arnaldo, 355, 8 degrees andar, CEP 01246-000, São Paulo, São Paulo, Brazil. atempone@ial.sp.gov.br
André Gustavo
AG
Tempone
Noemi Nosomi
NN
Taniwaki
Juliana Quero
JQ
Reimão
D000818:Animals; D000965:Antimony / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D002478:Cells, Cultured; D020128:Inhibitory Concentration 50; D018314:Leishmania infantum / Q000187:drug effects* / Q000648:ultrastructure*; D008253:Macaca mulatta; D017737:Macrophages, Peritoneal / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009553:Nimodipine / Q000494:pharmacology* / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism
D000981:Antiprotozoal Agents; D009569:Nitric Oxide; D009553:Nimodipine; D000965:Antimony