The antileishmanial agent licochalcone A interferes with the function of parasite mitochondria

Abstract

Leishmaniasis is a major and increasing public health problem, particularly in Africa, Asia, and Latin America (18,20), and it consists of a broad spectrum of diseases caused by different species of the protozoan genus Leishmania. More than 350 million people in the world are at risk of infection with Leishmania parasites. Over 12 million people are infected with different species of the parasite, and there are over 400,000 new cases each year (1). Recently, a dramatic increase in the number of visceral cases has been observed in southern Europe. The drugs available for the treatment of leishmaniasis are, in general, toxic and expensive and require long-term treatment (18). Large-scale clinical resistance against the most commonly used antileishmanial drug, antimonial agents, has been reported (19). The spread of drug resistance, combined with other shortcomings of the available antileishmanial drugs, emphasizes the importance of the development of new, effective, and safe drugs against leishmaniasis.Our previous studies have shown that licochalcone A, an oxygenated chalcone, inhibits the in vitro growth of both Leishmania major and L. donovani promastigotes, exhibits a remarkably strong ability to kill the intracellular parasites of L. major amastigotes (5), prevents lesion development in mice infected with L. major, and reduces the parasite load in the spleens and livers of hamsters infected with L. donovani (6). Licochalcone A also exhibits potent antimalarial activity both in vitro and in vivo (7). The mechanism by which licochalcone A kills the parasites and protects animals from infection is not known. We have observed that licochalcone A alters the ultrastructure of the mitochondria of Leishmania promastigotes (5). The present study was designed to examine this observation further and investigate the mechanism of action of the antileishmanial activity of licochalcone A. The ultrastructural changes in the promastigotes and amastigotes of L. major incubated with licochalcone A, the respiration of the parasites, and the activity of the parasite mitochondrial dehydrogenase were investigated. The data indicate that licochalcone A alters the ultrastructure and function of the mitochondria of Leishmania parasites. MATERIALS AND METHODSLicochalcone A. Licochalcone A was synthesized in our laboratory as previously described (6, 7), and it was dissolved in 2% dimethyl sulfoxide in medium 199 to prepare a working solution of 1 mg/ml.Parasite cultures. A World Health Organization reference vaccine strain of L. major (MHOM/IL/67/LRC-L437) originally isolated from a patient in Iran was cultured in medium 199 containing 10% heat-inactivated fetal calf serum. Incubation and growth of the parasite were carried out at 26ЊC. Promastigotes were harvested on culture day 4 and used.Ultrastructure studies. Electron microscopic studies were carried out to examine the effect of licochalcone A on the ultrastructure of both the promastigote and amastigote forms of the parasite as previously described (5). Briefly, for the promastig...

Trypanocidal and Leishmanicidal Properties of Substitution-Containing Chalcones

“…Nevertheless, the mechanisms by which the substitutioncontaining chalcones showed leishmanicidal and trypanocidal activities were not addressed in this work. Based on the literature, it can be predicted that chalcones could potentially inhibit the activity of fumarate reductase, succinate dehydrogenase, NADH dehydrogenase, or succinate-and NADH-cytochrome c reductases in the parasite mitochondria (2,3,7,19,20). Additional studies are in progress to address this hypothesis.…”

In Vivo Monitoring of Intracellular ATP Levels inLeishmania donovaniPromastigotes as a Rapid Method To Screen Drugs Targeting Bioenergetic Metabolism

“…Oxidative phosphorylation is essential to fulfill the minimal energetic requirements of the parasite (1, 22). Hence, drugs affecting mitochondrial ATP production, such as licochalcones or naphthoquinones, are potentially good leishmanicidal candidates (6,7,25). A decrease of the intracellular ATP is induced by these drugs since glycolysis is unable to fully counterbalance this decrease.…”

Bioactive Component of Licorice as an Antileishmanial Agent

“…The main target of licochalcone A was the mitochondrion of the parasite, whereas the host mitochondrion remained unaffected [48]. The reason for the same is still unknown but further studies suggested that the parasite respiratory rate was affected resulting in an overall decrease in parasite O 2 consumption and CO 2 production with a decrease in the activity of the mitochondrial dehydrogenases [50]. In vivo studies also showed high parasite elimination in in vivo studies upon intraperitoneal administration of licochalcone A as opposed to intralesional or oral administration [49].…”

“…The oxygenated chalcone, licochalcone A, has also been extensively studied to understand the mechanism of this compound as an antileishmanial agent [48][49][50]. Previous studies have shown its effect as antioxidant, antimicrobial and anti-tumor promoting properties [51,52].…”