Treatment with Fenofibrate plus a low dose of Benznidazole attenuates cardiac dysfunction in experimental Chagas disease

CEVEY, ÁGATA C.; MIRKIN, GERARDO A.; DONATO, MARTÍN; RADA, MARÍA J.; PENAS, FEDERICO N.; GELPI, RICARDO J.; GOREN, NORA B.

International Journal for Parasitology: Drugs and Drug Resistance

Elsevier Ltd

Lugar: Amsterdan; Año: 2017 vol. 7 p. 378 - 387

2211-3207

Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory re-sponse observed from the beginning of infection, is critical for the control of parasite proliferation and evolutionof Chagas disease. Peroxisome proliferator-activated receptors (PPAR)-α, are known to modulate inflammation.In this study we investigated whether a PPAR-αagonist, Fenofibrate, improves cardiac function and in-flammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with twoT. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, clearedparasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardio-myopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricularend-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced car-diac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-αand NOS2) and heartremodeling mediators (MMP-9 and CTGF), and reduced serum creatine kinase activity. The fact that Fenofibratepartially inhibited NOS2 expression and NO release in the presence of a PPAR-αnon-competitive inhibitor,suggested it also acted through PPAR-α-independent pathways. Since IκBαcytosolic degradation was inhibitedby Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate thatFenofibrate acts through PPAR-α-dependent and -independent pathways.Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse thecardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasiteclearance in an experimental model of Chagas disease.