Nitric oxide donor trans-[RuCl([15]aneN)NO] as a possible therapeutic approach for Chagas' disease.
OBJECTIVE
Benznidazole (Bz) is the therapy currently available for clinical treatment of Chagas' disease. However, many strains of Trypanosoma cruzi parasites are naturally resistant. Nitric oxide (NO) produced by activated macrophages is crucial to the intracellular killing of parasites. Here, we investigate the in vitro and in vivo activities against T. cruzi, of the NO donor, trans-[RuCl([15]aneN(4))NO](2+).


METHODS
Trans-[RuCl([15]aneN(4))NO](2+)was incubated with a partially drug-resistant T. cruzi Y strain and the anti-proliferative (epimastigote form) and trypanocidal activities (trypomastigote and amastigote) evaluated. Mice were treated during the acute phase of Chagas' disease. The anti-T. cruzi activity was evaluated by parasitaemia, survival rate, cardiac parasitism, myocarditis and the curative rate.


RESULTS
Trans-[RuCl([15]aneN(4))NO](2+) was 10- and 100-fold more active than Bz against amastigotes and trypomastigotes respectively. Further, trans-[RuCl([15]aneN(4))NO](2+) (0.1 mM) induced 100% of trypanocidal activity (trypomastigotes forms) in vitro. Trans-[RuCl([15]aneN(4))NO](2+) induced permanent suppression of parasitaemia and 100% survival in a murine model of acute Chagas' disease. When the drugs were given alone, parasitological cures were confirmed in only 30 and 40% of the animals treated with the NO donor (3.33 micromol.kg(-1).day(-1)) and Bz (385 micromol.kg(-1).day(-1)), respectively, but when given together, 80% of the animals were parasitologically cured. The cured animals showed an absence of myocarditis and a normalisation of cytokine production in the sera. In addition, no in vitro toxicity was observed at the tested doses.


CONCLUSIONS
These findings indicate that trans-[RuCl([15]aneN(4))NO](2+)is a promising lead compound for the treatment of human Chagas' disease.
Department of Biochemistry and Immunology, School of Medicine at Ribeirão Preto, São Paulo, Brazil. pauloguedes@usp.br <pauloguedes@usp.br>
Paulo M M
PM
Guedes
Fabiana S
FS
Oliveira
Fredy R S
FR
Gutierrez
Grace Kelly
GK
da Silva
Gerson Jhonatan
GJ
Rodrigues
Lusiane Maria
LM
Bendhack
Douglas W
DW
Franco
Maria A
MA
Do Valle Matta
Dario S
DS
Zamboni
Roberto Santana
RS
da Silva
João Santana
JS
Silva
D000818:Animals; D002598:Chagas Cardiomyopathy / Q000188:drug therapy / Q000469:parasitology; D014355:Chagas Disease / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology; D004195:Disease Models, Animal; D004351:Drug Resistance; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000633:toxicity; D009593:Nitroimidazoles / Q000494:pharmacology / Q000633:toxicity; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000633:toxicity; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D015996:Survival Rate; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects*
D020030:Nitric Oxide Donors; D009593:Nitroimidazoles; D009942:Organometallic Compounds; D014344:Trypanocidal Agents; C494411:chloronitrosyl(1,4,8,12-tetraazacyclopentadecane)ruthenium(III); D009569:Nitric Oxide; C009999:benzonidazole