Antiparasitic Activity of Plumbago auriculata Extracts and Its Naphthoquinone Plumbagin against Trypanosoma cruzi

by Selleckchem | Aug 04 2023

Chagas disease (CD) caused by the protozoan Trypanosoma cruzi affects more than six million people worldwide. Treatment is restricted to benznidazole (Bz) and nifurtimox (Nf) that display low activity in the later chronic stage besides triggering toxic events that result in treatment abandonment. Therefore, new therapeutic options are necessary. In this scenario, natural products emerge as promising alternatives to treat CD. In the family Plumbaginaceae, Plumbago sp. exhibits a broad spectrum of biological and pharmacological activities. Thus, our main objective was to evaluate, in vitro and in silico, the biological effect of crude extracts of root and of aerial parts of P. auriculata, as well as its naphthoquinone Plumbagin (Pb) against T. cruzi. The phenotypic assays revealed potent activity of the root extract against different forms (trypomastigote and intracellular forms) and strains (Y and Tulahuen), with a compound concentration that reduced 50% of the number of the parasite (EC50) values ranging from 1.9 to 3.9 µg/mL. In silico analysis showed that Pb is predicted to have good oral absorption and permeability in Caco2 cells, besides excellent probability of absorption by human intestinal cells, without toxic or mutagenic potential effects, not being predicted as a substrate or inhibitor of P-glycoprotein. Pb was as potent as Bz against intracellular forms and displayed a superior trypanosomicidal effect (about 10-fold) in bloodstream forms (EC50 = 0.8 µM) as compared to the reference drug (8.5 µM). The cellular targets of Pb on T. cruzi were evaluated using electron microscopy assays and the findings on bloodstream trypomastigotes showed several cellular insults related to the autophagic process. Regarding toxicity in mammalian cells, the root extracts and the naphthoquinone present a moderate toxic profile on fibroblasts and cardiac cell lines. Then, aiming to reduce host toxicity, the root extract and Pb were tested in combination with Bz, and the data showed additive profiles with the sum of the fractional inhibitory concentration indexes (ΣFICIs) being 1.45 and 0.87, respectively. Thus, our work reveals the promising antiparasitic activity of Plumbago auriculata crude extracts and its purified naphthoquinone Plumbagin against different forms and strains of Trypanosoma cruzi in vitro.

Comments:

Chagas disease (CD) is a serious illness caused by the protozoan parasite Trypanosoma cruzi. It affects millions of people worldwide, and the current treatment options, benznidazole (Bz) and nifurtimox (Nf), have limited effectiveness in the later chronic stage and can cause toxic side effects leading to treatment abandonment. Therefore, there is a need for new therapeutic alternatives. Natural products, such as those found in the Plumbaginaceae family, offer promising prospects for CD treatment.

Researchers aimed to evaluate the in vitro and in silico effects of crude extracts from the roots and aerial parts of Plumbago auriculata, as well as its naphthoquinone compound Plumbagin (Pb), against T. cruzi. Phenotypic assays demonstrated potent activity of the root extract against various forms and strains of the parasite, with EC50 values (the concentration that reduces parasite numbers by 50%) ranging from 1.9 to 3.9 µg/mL. In silico analysis indicated that Pb has favorable characteristics for oral absorption, permeability in Caco2 cells, and absorption by human intestinal cells. It was not predicted to have toxic or mutagenic effects and was not identified as a substrate or inhibitor of P-glycoprotein, a protein involved in drug transport.

Pb showed similar potency to Bz against intracellular forms of T. cruzi and exhibited a superior trypanosomicidal effect in bloodstream forms, with an EC50 value of 0.8 µM compared to 8.5 µM for the reference drug. Electron microscopy assays revealed that Pb induced several cellular insults related to the autophagic process in bloodstream trypomastigotes, the parasite's life stage found in the bloodstream. Regarding toxicity in mammalian cells, both the root extracts and Pb exhibited a moderate toxic profile on fibroblasts and cardiac cell lines.

To mitigate host toxicity, the root extract and Pb were tested in combination with Bz. The results demonstrated additive effects, with the sum of the fractional inhibitory concentration indexes (ΣFICIs) being 1.45 and 0.87, respectively.

Overall, this study highlights the promising antiparasitic activity of Plumbago auriculata crude extracts and its purified naphthoquinone, Plumbagin, against various forms and strains of Trypanosoma cruzi in vitro. Further research and development are warranted to explore the potential of these natural products as alternative treatments for Chagas disease.