Activities of psilostachyin A and cynaropicrin against Trypanosoma cruzi in vitro and in vivo.
In vitro and in vivo activities against Trypanosoma cruzi were evaluated for two sesquiterpene lactones: psilostachyin A and cynaropicrin. Cynaropicrin had previously been shown to potently inhibit African trypanosomes in vivo, and psilostachyin A had been reported to show in vivo effects against T. cruzi, albeit in another test design. In vitro data showed that cynaropicrin was more effective than psilostachyin A. Ultrastructural alterations induced by cynaropicrin included shedding events, detachment of large portions of the plasma membrane, and vesicular bodies and large vacuoles containing membranous structures, suggestive of parasite autophagy. Acute toxicity studies showed that one of two mice died at a cynaropicrin dose of 400 mg/kg of body weight given intraperitoneally (i.p.). Although no major plasma biochemical alterations could be detected, histopathology demonstrated that the liver was the most affected organ in cynaropicrin-treated animals. Although cynaropicrin was as effective as benznidazole against trypomastigotes in vitro, the treatment (once or twice a day) of T. cruzi-infected mice (up to 50 mg/kg/day cynaropicrin) did not suppress parasitemia or protect against mortality induced by the Y and Colombiana strains. Psilostachyin A (0.5 to 50 mg/kg/day given once a day) was not effective in the acute model of T. cruzi infection (Y strain), reaching 100% animal mortality. Our data demonstrate that although it is very promising against African trypanosomes, cynaropicrin does not show efficacy compared to benznidazole in acute mouse models of T. cruzi infection.
Laboratório de Biologia Celular, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
Cristiane França
CF
da Silva
Denise da Gama Jaen
Dda G
Batista
Julianna Siciliano
JS
De Araújo
Marcos Meuser
MM
Batista
Jessica
J
Lionel
Elen Mello
EM
de Souza
Erica Ripoll
ER
Hammer
Patricia Bernardino
PB
da Silva
Maria
M
De Mieri
Michael
M
Adams
Stefanie
S
Zimmermann
Matthias
M
Hamburger
Reto
R
Brun
Wolfgang
W
Schühly
Maria de Nazaré Correia
Mde N
Soeiro
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D014355:Chagas Disease / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology; D007783:Lactones / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000469:parasitology / Q000473:pathology; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009593:Nitroimidazoles / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D012717:Sesquiterpenes / Q000494:pharmacology; D016019:Survival Analysis; D017211:Treatment Failure; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure
D007783:Lactones; D009593:Nitroimidazoles; D012717:Sesquiterpenes; D014344:Trypanocidal Agents; C568085:psilostachyin A; C075687:cynaropicrin; C009999:benzonidazole