Impact of mitochondrial uncoupler on oxidative stress and acute Chagas heart disease

Abstract

By uncoupling oxidative phosphorylation, 2,4-Dinitrophenol (DNP) attenuates reactive oxygen species (ROS) biosynthesis, which are known to aggravate infectious myocarditis in Chagas disease. Thus, the impact of DNP-based chemotherapy on Trypanosoma cruzi-induced acute myocarditis was investigated. C56BL/6 mice uninfected and infected untreated and treated with 100 mg/kg benznidazole (Bz, reference antiparasitic drug), 5 and 10 mg/kg DNP by gavagem during 20 days were investigated. Twenty-four hours after the last treatment, the animals were euthanized and the heart was collected for microstructural, immunological, biochemical and molecular analyses. T. cruzi infection induced marked parasitemia, systemic inflammation (e.g., cytokines and anti-T. cruzi IgG upregulation), cardiac parasite load (T. cruzi DNA), oxidative stress, inflammatory infiltrate and microstructural myocardial damage in untreated mice. DNP treatment aggravated parasitemia, heart parasitism and microstructural damage, which were markedly attenuated by Bz. Like thus drug, 10 mg/kg DNP was also effective in attenuating ROS (total ROS, H2O2 and O2 - ), nitric oxide (NO), lipid (malondialdehyde - MDA) and protein oxidation (protein carbonyl - PCn), TNF, IFN-γ, IL-10, and MCP-1/CCL2, anti-T. cruzi IgG, cardiac troponin I levels, as well as inflammatory infiltrate and cardiac damage in T. cruzi-infected mice. Taken together, our findings indicate that DNP acts as a pharmacological risk factor, aggravating parasitemia, heart parasitism and microstructural cardiomyocytes damage in T. cruzi-infected mice. These responses were potentially related to the antioxidant and anti-inflammatory properties of DNP in the absence of trypanocidal effect, which favors parasitism by weakening the host's pro-oxidant and pro-inflammatory antiparasitic mechanisms. Conversely, Bz-induced cardioprotective effects were associated with effective anti-inflammatory and antiparasitic responses, which protect against heart parasitism, oxidative stress and microstructural damage in Chagas disease.