Effect of Apigenin on Leishmania amazonensis Is Associated with Reactive Oxygen Species Production Followed by Mitochondrial Dysfunction

Abstract

Leishmaniasis is an important neglected disease caused by protozoa of the genus Leishmania that affects more than 12 million people worldwide. Leishmaniasis treatment requires the administration of toxic and poorly tolerated drugs, and parasite resistance greatly reduces the efficacy of conventional medications. Apigenin (1), a naturally occurring plant flavone, has a wide range of reported biological effects. In this study, antileishmanial activity of 1 in vitro was investigated, and its mechanism of action against Leishmania amazonensis promastigotes was described. Treatment with 1 for 24 h resulted in concentration-dependent inhibition of cellular proliferation (IC50 = 23.7 μM) and increased reactive oxygen species (ROS) generation. Glutathione and N-acetyl-l-cysteine protected L. amazonensis from the effects of 1 and reduced ROS levels after the treatment. By contrast, oxidized glutathione did not reduce the levels of ROS caused by 1 by not preventing the proliferation inhibition. Apigenin 1 also induced an extensive swelling in parasite mitochondria, leading to an alteration of the mitochondrial membrane potential, rupture of the trans-Golgi network, and cytoplasmic vacuolization. These results demonstrate the leishmanicidal effect of 1 and suggest the involvement of ROS leading to mitochondrial collapse as part of the mechanism of action.

Comparative Analysis of the Antibacterial Activity and HPLC Phytochemical Screening of the Brazilian Red Propolis and the Resin of Dalbergia ecastaphyllum

“…Quercetin and luteolin were also found in D. ecastaphyllum resin from previous studies using samples from Alagoas . Neuroprotective, anticancer, anti‐inflammatory, antioxidant, antimicrobial and antileishmania are among the bioactivities reported for the compounds identified in our study …”

“…reported for the compounds identified in our study. [31][32][33][34][35][36] The hydroethanolic extract of red propolis from the Brazilian states of Alagoas, Pernambuco, Paraíba and Sergipe has been tested against Gram-positive and Gram-negative bacteria. [16,37,38] However, reports about the antibacterial activity of the plant resin produced by Dalbergia ecastaphyllum remains scarce.…”

Oral Efficacy of Apigenin against Cutaneous Leishmaniasis: Involvement of Reactive Oxygen Species and Autophagy as a Mechanism of Action

“…The activity of apigenin against the promastigote form of L . amazonensis has been described [ 17 ]. To determine the effects of apigenin on the interaction of L .…”

Effects of nitro-heterocyclic derivatives against Leishmania (Leishmania) infantum promastigotes and intracellular amastigotes

“…One hypothesis is that the compounds of the BSF group could act as a NO donor, in a cellular stress situation, as with cells infected with L. L. infantum in our experiment. The mechanism NO exerts on cytotoxicity activity is not well understood, but it may be by inhibition of mitochondrial respiration, glycolysis, peroxidation of membrane lipids, inactivation of peroxidases and arginases (Fonseca-Silva et al, 2015;Ghosh et al, 2015;da Silva et al, 2015;Giudice et al,, 2007;Grandoni and Ascendi, 2004;Vickers et al, 2004).…”