Paroxetine activity against Trypanosoma cruzi: in vitro and in vivo studies.

BACKGROUND

Chagas disease (CD) lacks effective therapy. However, the long time and high financial investments for the development of new drugs are limiting obstacles. The repositioning of drugs is an interesting approach for novel antiparasitic medicines. Previous results suggest that paroxetine (PXT) may represent a promising anti-Trypanosoma cruzi agent.

OBJECTIVES

Our aim was to evaluate the activity and cellular targets of PXT on T. cruzi infection in vitro and in vivo.

METHODS

PXT and benznidazole (BZ) were assayed against intracellular and bloodstream forms for different periods of incubation by colorimetric and light microscopy analysis. Bloodstream forms were exposed to PXT and observed by transmission electron microscopy. PXT alone and in combination with BZ was evaluated as an acute mouse model of T. cruzi infection.

FINDINGS: PXT is active (EC50 = 2.18 μM) against amastigotes of T. cruzi (Tulahuen-β gal strain), resulting in > 99% suppression of parasitism after 168 h of drug exposure. Upon bloodstream forms (Y strain), PXT was effective, displaying EC50 values of 8.90 and 4.27 μM after 2 and 24 h of incubation, respectively, revealing a rapid trypanocidal activity. PXT triggered ultrastructural alterations on trypomastigotes, including cytoplasmic disorganization, numerous contractile vacuoles besides damage on the mitochondria and paraflagellar stem. The proof of concept using a mouse model of acute T. cruzi infection demonstrates that although the parasitaemia was suppressed, PXT was unable to protect against mortality.

MAIN

CONCLUSIONS

Our findings demonstrate the activity of PXT against T. cruzi and reinforces the relevance of drug repositioning for CD.