The natural
polyamines are ubiquitous polycationic compounds that play important
biological functions in cell growth and differentiation. In the case of protozoan species that are causative agents of important human diseases such as
Leishmaniasis, an exogenous supply of
polyamines supports parasite proliferation. In the present study, we have investigated the effect of three
polyamine derivatives, (namely bis-naphthalimidopropyl
putrescine (
BNIPPut),
spermidine (
BNIPSpd) and
spermine (
BNIPSpm)), on the proliferative stages of Leishmania infantum, the causative agent of
visceral leishmaniasis in the Mediterranean basin. A significant reduction of promastigotes and axenic amastigotes growth was observed in the presence of increasing concentrations of the drugs, although the mechanisms leading to the parasite growth arrest seems to be different. Indeed, by using a number of biochemical approaches to analyse the alterations that occurred during early stages of parasite-drug interaction (i.e. membrane
phosphatidylserine exposure measured by
annexin V binding, DNA fragmentation, deoxynucleotidyltranferase-mediated dUTP end labelin (TUNEL), mitochondrial transmembrane potential loss), we showed that the drugs had the capacity to induce the death of promastigotes by a mechanism that shares many features with metazoan apoptosis. Surprisingly, the amastigotes did not behave in a similar way to promastigotes. The
drug inhibitory effect on amastigotes growth and the absence of
propidium iodide labelling may suggest that the compounds are acting as
cytostatic substances. Although, the mechanisms of action of these compounds have yet to be elucidated, the above data show for the first time that
polyamine derivatives may act differentially on the Leishmania parasite stages. Further chemical modifications are needed to make the
polyamine derivatives as well as other analogues able to target the amastigote stage of the parasite.