Effectiveness of the repurposed drug isotretinoin in an experimental murine model of Chagas disease

RIAL, MS; REIGADA, CHANTAL; PRADO, N; BUA, J; ESTEVA, MONICA; PEREIRA, CA; FICHERA, LE

ACTA TROPICA

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2023

0001-706X

Benznidazole and nifurtimox are the drugs currently used for the treatment of24 Chagas disease, however its side effects may affect patient adherence. In the25 search for new alternative therapies, we previously identified isotretinoin (ISO),26 an FDA-approved drug widely used for the treatment of severe acne through a27 drug repurposing strategy. ISO shows a strong activity against Trypanosoma28 cruzi parasites in the nanomolar range, and its mechanism of action is through29 the inhibition of T. cruzi polyamine and amino acid transporters from the Amino30 Acid/Auxin Permeases (AAAP) family. In this work, a murine model of chronic31 Chagas disease (C57BL/6J mice), intraperitoneally infected with T. cruzi32 Nicaragua isolate (DTU TcI), were treated with different oral administrations of33 ISO: daily doses of 5 mg/kg/day for 30 days and weekly doses of 10 mg/kg34 during 13 weeks. The efficacy of the treatments was evaluated by monitoring35 blood parasitemia by qPCR, anti-T. cruzi antibodies by ELISA, and cardiac36 abnormalities by electrocardiography. No parasites were detected in blood after37 any of the ISO treatments. The electrocardiographic study of the untreated38 chronic mice showed a significant decrease in heart rate, while in the treated39 mice this negative chronotropic effect was not observed. Atrioventricular nodal40 conduction time in untreated mice was significantly longer than in treated41 animals. Mice treated even with ISO 10 mg/kg dose every 7 days, showed a42 significant reduction in anti-T. cruzi IgG levels. In conclusion, the intermittent43 administration of ISO 10 mg/kg would improve myocardial compromise during44 the chronic stage.