Amiodarone Inhibits Trypanosoma cruzi Infection and Promotes Cardiac Cell Recovery with Gap Junction and Cytoskeleton Reassembly In Vitro

Abstract

We present the results of the first detailed study of the antiproliferative and ultrastructural effects of amiodarone on Trypanosoma cruzi, the causative agent of Chagas' disease. Moreover, we report the effects of this compound on the recovery of F-actin fibrils, connexin43, and contractility in T. cruzi-infected cardiac myocytes. Amiodarone is the most prescribed class III antiarrhythmic agent and is frequently used for the symptomatic treatment of Chagas' disease patients with cardiac compromise. In addition, recent studies identified its antifungal and antiprotozoal activities, which take place through Ca 2؉ homeostasis disruption and ergosterol biosynthesis blockade. We tested different concentrations of amiodarone (2.5 to 10 M) on infected primary cultures of heart muscle cells and observed a dose-and time-dependent effect on growth of the clinically relevant intracellular amastigote form of T. cruzi. Ultrastructural analyses revealed that amiodarone had a profound effect on intracellular amastigotes, including mitochondrial swelling and disorganization of reservosomes and the kinetoplast and a blockade of amastigote-trypomastigote differentiation. Amiodarone showed no toxic effects on host cells, which recovered their F-actin fibrillar organization, connexin43 distribution, and spontaneous contractility concomitant with the drug-induced eradication of the intracellular parasites. Amiodarone is, therefore, a promising compound for the development of new drugs against T. cruzi.

Effects of amiodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi

“…Lazardi et al [26] previously described the presence of autophagic vacuoles in amastigotes treated with other sterol biosynthesis inhibitors such as ketoconazole and terbinafine. Using AMD against intracellular T. cruzi amastigotes, Adesse et al [27] described alterations such as mitochondrial swelling, reservosomes and kinetoplast disorganisation after 144 h. The fact that these effects were not observed in this study is likely due to the type of host cell used; Adesse et al [27] used murine cardiomyocytes, whereas the current study used peritoneal macrophages.…”

The TGF-β Pathway as an Emerging Target for Chagas Disease Therapy

“…73 A recent in vitro study showed that amiodarone promotes heart-cell recovery and gap-junction reconfiguration. 74 These data stress the need for further retrospective and prospective studies on the effects of amiodarone on patients with Chagas disease that would take into account their genetic polymorphism in the TGFB1 gene and their possibly correlated circulating TGF-β1 levels.…”

Amiodarone impairs trafficking through late endosomes inducing a Niemann-Pick C-like phenotype

“…The interference of amiodarone and its derivatives with the endocytic pathway, besides its obvious clinical interest in the field of cardiology, might represent the subject of future investigations in unrelated areas, in particular for the development of novel strategies against infectious agents. Indeed amiodarone interferes in vitro with the life cycle of the SARS coronavirus [6], mitigates in an in vivo model the effects of the encephalomyocarditis virus [61] and has been shown to be of value in the treatment of the Trypanosomacruzi infection [62]. In addition, it could be of interest studying the effect of amiodarone on Dengue infection, because it has recently been shown that LBPA (whose distribution may be modified by amiodarone) is an obligatory cofactor for the entry of the Dengue virus into target cells [63].…”