Novel therapeutic approach: Low-dose benznidazole treatment results in parasite clearance and attenuates heart inflammatory reaction in an experimental model of Chagas disease.

CEVEY AGATA; MIRKIN GERARDO A.; FEDERICO PENAS; GOREN, NORA

Buenos Aires

Congreso; IV Meeting Lasid-SAI; 2015

SAI

Chagas disease, caused by Trypanosoma cruzi, is the main cause of dilated cardiomyopathy in theAmericas. Antiparasitic treatment relies mostly on benznidazole (Bzl) due to Nifurtimox shortage orunavailability. Both induce adverse drug effects (ADE) of varied severity in many patients, which lead totreatment discontinuation or abandonment. Since dosage may influence ADE, we aimed to assess Bzlefficacy in terms of parasiticidal and anti-inflammatory activity, using doses lower than those previouslyreported.MethodsBALB/c mice infected with the T. cruzi RA strain were treated with different doses of Bzl. Parasitaemia,mortality and weight change were assessed. Parasite load, tissue infiltrates and inflammatory mediatorswere studied in the heart. Serum creatine kinase was determined as a marker of heart damage. Theinfection-independent anti-inflammatory properties of Bzl were studied in an in vitro model of LPS-treated cardiomyocyte culture.ResultsTreatment with 25 mg/Kg/day Bzl turned the parasitological parameters negative, induced a significantdecrease in IL-1β, IL-6 and NOS2 in the heart and CK activity in serum, to normal levels. No mortalitywas observed in infected treated mice. Primary cultured cardiomyocytes treated with Bzl showed thatinflammatory mediators were reduced via inhibition of the NF-κB pathway.Conclusions A Bzl dose lower than that previously reported for the treatment of experimental Chagasâ?? disease exertsadequate antiparasitic and anti-inflammatory effects leading to parasite clearance and tissue healing.This may be relevant to reassess the dosage currently used for the treatment of human Chagasâ??disease, aiming to reduce ADE.