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

Abstract

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.

Experimental transmission of Leishmania (Leishmania) amazonensis to immunosuppressed mice through the bite of Lutzomyia longipalpis (Diptera: Psychodidae) results in cutaneous leishmaniasis

“…The parasitic loads of the spleen, liver, inguinal lymph nodeand foot injuries were determined using the limiting dilution method 26 . This assay was performed in duplicate and incubated at 27 °C.…”

Exploiting knowledge on pharmacodynamics-pharmacokinetics for accelerated anti-leishmanial drug discovery/development

“…Acknowledging the oxidative potential of miltefosine, recently, intraperitoneal treatment with miltefosine and ascorbic acid proved efficacious in abrogating the damaging effects caused by miltefosine. Thus, ascorbic acid mitigated the oxidative damages by miltefosine and efficiently reduced the parasitic burden [87].…”

Diversification of health-promoting phytochemicals in radish (Raphanus raphanistrum) and kale (Brassica oleracea) micro-greens using high light bio-fortification

“…Ascorbic acid is a non-enzymatic, water soluble antioxidant obtained from the diet and essential to humans because of its role in several physiological activities [69]. The antioxidant activity of ascorbic acid has been demonstrated to prevent the development of certain types of cancer, cardiovascular diseases and other illnesses related to oxidative stress [70,71]. Furthermore, ascorbic acid can convert reactive compounds to less toxic and more easily excreted products, as well as capturing free radicals before they interact with other molecules, protecting them from oxidative damage [72,73].…”