Ascorbic acid reduces the genetic damage caused by miltefosine (hexadecylphosphocholine) in animals infected by Leishmania (Leishamnia) infantum without decreasing its antileishmanial activity

Leishamaniasis is a neglected disease caused by over 20 Leishmania species, occurring in more than a hundred countries. Miltefosine (hexadecylphosphocholine) is the single oral drug used in treatment for leshmaniases, including cases of infections resistant to pentavalent antimony. Our group has recently demonstrated the ability of miltefosine to cause genomic lesions by DNA oxidation. Acknowledging that antioxidant compounds can potentially modulate Reactive Oxygen Species (ROS), our study verified whether ascorbic acid reduces the genotoxic and mutagenic effects caused by miltefosine, and whether it interferes with drug efficacy. For this purpose, uninfected Swiss mice received simultaneous (single dose treatment) miltefosine and ascorbic acid (gavage and intraperitoneally), besides pre and post treatments (ascorbic acid 24 h before and after drug administration); furthermore, Balb/c mice infected with Leishmania infantum received miltefosine plus ascorbic acid (repeated doses treatment). We conducted comet assays, micronucleus tests, dosages of superoxide dismutase enzyme and parasitic burden by the limiting dilution assay. We observed that ascorbic acid administered intraperitoneally displayed a protective effect over damage caused by miltefosine. However, this effect was not not observed when the same doses were administered via gavage, possibly due to low serum levels of this antioxidant. Ascorbic acid's protective effect reinforces that miltefosine damages DNA by oxidizing its nitrogenous bases, which is reduced by ascorbic acid due to its ability of protecting genetic material from the action of ROS. Therefore, our results show that this drug is efficient in reducing parasitic burden of L. infantum.