Effects of clomipramine on Trypanosoma cruzi infection in mice

Trypanosoma cruzi, widely distributed in Latin American countries, provokes Chagas disease, characterized by cardiomyopathy and mega-viscera. The drug s used currently for treatment of acute Chagas disease are highly toxic; th e side-effects are undesirable and patients may abandon treatment. We have previously demonstrated that clomipramine (CLO) exerts trypanocidal effects upon epimastigotes and trypomastigotes in vitro with anticalmodulin activi ty. The present study analyses the effectiveness of CLO treatment in mice i nfected with a low number of T. cruzi, an animal model that reproduces acut e, indeterminate and chronic phases of this trypanosomiasis. In this work, our results demonstrated that CLO 5 mg/kg daily for 30 days, or 2 doses of CLO 40 mg/kg given intraperitoneally at 1 h and 7 days after infection, was not toxic for the host, but was effective against the parasite in that par asitaemias became negative and only mild heart structural and electrocardio graphic alterations were detected in the chronic phase in the group treated with CLO 5 mg/kg. In mice treated with CLO 40 mg/kg, none of these alterat ions was detected. Cardiac beta receptor density and affinity returned to n ormal in the chronic stage in both experimental groups, T. cruzi enzymes su ch as calmodulin and trypanothione reductase represent potential drug targe ts. It has been reported that both can be inhibited by CLO, a tricyclic dru g used in clinical therapeutics. We have shown that CLO strongly decreased the mortality rate and electrocardiographic alterations; in addition cardia c beta receptor density and heart histology returned to, or close to, norma lity 135 days post infection. These results clearly demonstrated that CLO t reatment modified significantly the natural evolution of T cruzi infection.