Amiodarone inhibits Trypanosoma cruzi infection and promotes cardiac cell 1 recovery with gap junction and cytoskeleton reassembly in vitro

25 We present the results of the first detailed study of the antiproliferative and 26 ultrastructural effect of amiodarone on Trypanosoma cruzi, the causative agent of 27 Chagas' disease. Moreover, we report the effects of this compound on the recovery of 28 F-actin fibrils, connexin43 and contractility in T. cruzi infected cardiac myocytes. 29 Amiodarone is the most prescribed class III antiarrhythmic agent and is frequently 30 used for the symptomatic treatment of Chagas' disease patients with cardiac 31 compromise. In addition, recent studies identified its antifungal and antiprotozoal 32 activities, which take place through Ca 2+ homeostasis disruption and ergosterol 33 biosynthesis blockage. We tested different concentrations of amiodarone (2.5-10µM) 34 on infected primary cultures of heart muscle cells and observed a dose-and time-35 dependent effect on growth of the clinically relevant intracellular amastigote form of T. 36 cruzi. Ultrastructural analyses revealed that amiodarone had a profound effect on 37 intracellular amastigotes, including mitochondrial swelling and disorganization of 38 reservosomes and the kinetoplast and blockade of amastigote-trypomastigote 39 differentiation. Amiodarone showed no toxic effects on host cells, which recovered 40 their F-actin fibrilar organization, connexin43 distribution and spontaneous contractility 41 concomitant with the drug-induced eradication of the intracellular parasites. 42 Amiodarone is, therefore, a promising compound for the development of new drugs 43 against T. cruzi.