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

CEVEY, A; MIRKIN, GA; PENAS, F; GOREN, NB

Buenos Aires

Congreso; LXIII Argentinean Society for Immunology Meeting, II French-Argentinean Immunology meeting; 2015

Sociedad Argentina de Inmunología

Background and objectives: Chagas? disease, caused byTrypanosoma cruzi, is the main cause of dilated cardiomyopathyin the Americas. Antiparasitic treatment relies mostly onbenznidazole (Bzl) due to Nifurtimox shortage or unavailability.Both induce adverse drug effects (ADE) of varied severity inmany patients, which lead to treatment discontinuation orabandonment. Since dosage may influence ADE, we aimed toassess Bzl efficacy in terms of parasiticidal and anti-inflammatoryactivity, using doses lower than those previously reported.Methods: BALB/c mice infected with the T. cruzi RA strain weretreated with different doses of Bzl. Parasitaemia, mortality andweight change were assessed. Parasite load, tissue infiltrates andinflammatory mediators were studied in the heart. Serum creatinekinase was determined as a marker of heart damage. Theinfection-independent anti-inflammatory properties of Bzl werestudied in an in vitro model of LPS-treated cardiomyocyte culture.Results: Treatment with 25 mg/Kg/day Bzl turned theparasitological parameters negative, induced a significant decreasein IL-1β, IL-6 and NOS2 in the heart and CK activity in serum, tonormal levels. No mortality was observed in infected treated mice.Primary cultured cardiomyocytes treated with Bzl showed thatinflammatory mediators were reduced via inhibition of the NF-κBpathway.Conclusions: A Bzl dose lower than that previously reported forthe treatment of experimental Chagas? disease exerts adequateantiparasitic and anti-inflammatory effects leading to parasiteclearance and tissue healing. This may be relevant to reassess thedosage currently used for the treatment of human Chagas? disease,aiming to reduce ADE.