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Activity of Combinations of Antioxidants and Anthelmintic Drugs against the Adult Stage of Schistosoma mansoni.

ABSTRACT: Schistosomiasis remains a major neglected tropical disease. The treatment and control of schistosomiasis rely on a single drug, praziquantel (PZQ). Despite its efficacy, treatment with PZQ presents some major drawbacks including an inability of the chemotherapy to reverse disease-induced fibrosis and the prospect of the emergence of drug resistance. Here, we investigated a novel therapeutic approach with antioxidant biomolecules in combination with PZQ against the adult developmental stage of Schistosoma mansoni and oviposition in vitro, given that this therapeutic approach achieved synergistic/additive activity against larval schistosomes. The antioxidants curcumin and oxadiazole per se exhibited antischistosomal activity against adult worms leading to severe morphological alterations and death. Additionally, the antioxidant flavone combined with vandetanib or imatinib improved antischistosomal activity against adult forms. By contrast, however, these antioxidant-anthelmintic combinations were not as effective against adults in comparison to larval schistosomes. Nevertheless, the antioxidants alone or combined with drugs inhibited oviposition.

SUBMITTER: Gouveia MJ

PROVIDER: S-EPMC7429017 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Activity of Combinations of Antioxidants and Anthelmintic Drugs against the Adult Stage of <i>Schistosoma mansoni</i>.

Gouveia Maria João MJ Brindley Paul J PJ Gärtner Fátima F Vale Nuno N

Journal of parasitology research 20200806

Schistosomiasis remains a major neglected tropical disease. The treatment and control of schistosomiasis rely on a single drug, praziquantel (PZQ). Despite its efficacy, treatment with PZQ presents some major drawbacks including an inability of the chemotherapy to reverse disease-induced fibrosis and the prospect of the emergence of drug resistance. Here, we investigated a novel therapeutic approach with antioxidant biomolecules in combination with PZQ against the adult developmental stage of <i ...[more]

PMID: 32832132

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Project description:BackgroundTreatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. Despite its celebrated performance for treatment and control of schistosomiasis and other platyhelminth infections, praziquantel has some shortcomings and the inability of this drug to counteract disease sequelae prompts the need for novel therapeutic strategies.MethodsUsing a host-parasite model involving Biomphalaria glabrata and Schistosoma mansoni we established mechanical transformation of S. mansoni cercariae into newly transformed schistosomula (NTS) and characterized optimal culture conditions. Thereafter, we investigated the antischistosomal activity and ability of the antioxidants N-acetylcysteine (NAC) and resveratrol (RESV) to augment the performance of praziquantel and/or artesunate (AS) against larval stages of the parasite. Drug effects were evaluated by using an automated microscopical system to study live and fixed parasites and by transmission electron microscopy (TEM).ResultsTransformation rates of cercariae to schistosomula reached ~ 70% when the manipulation process was optimized. Several culture media were tested, with M199 supplemented with HEPES found to be suitable for S. mansoni NTS. Among the antioxidants studied, RESV alone or combined with anthelminthic drugs achieved better results rather N-acetylcysteine (NAC). TEM observations demonstrated that the combination of AS + RESV induced severe, extensive alterations to the tegument and subtegument of NTS when compared to the constituent compounds alone. Two anthelmintic-antioxidant combinations, praziquantel-resveratrol [combination index (CI) = 0.74] and artesunate-resveratrol (CI = 0.34) displayed moderate and strong synergy, respectively.ConclusionsThe use of viability markers including staining with propidium iodide increased the accuracy of drug screening assays against S. mansoni NTS. The synergies observed might be the consequence of increased action by RESV on targets of AS and PZQ and/or they may act through concomitantly on discrete targets to enhance overall antischistosomal action. Combinations of active agents, preferably with discrete modes of action including activity against developmental stages and/or the potential to ameliorate infection-associated pathology, might be pursued in order to identify novel therapeutic interventions.

Project description:BACKGROUND:Whipworms and blood flukes combined infect almost one billion people in developing countries. Only a handful of anthelmintic drugs are currently available to treat these infections effectively; there is therefore an urgent need for new generations of anthelmintic compounds. Medicinal plants have presented as a viable source of new parasiticides. Ajania nubigena, the Bhutanese daisy, has been used in Bhutanese traditional medicine for treating various diseases and our previous studies revealed that small molecules from this plant have antimalarial properties. Encouraged by these findings, we screened four major compounds isolated from A. nubigena for their anthelmintic properties. METHODOLOGY/PRINCIPAL FINDINGS:Here we studied four major compounds derived from A. nubigena for their anthelmintic properties against the nematode whipworm Trichuris muris and the platyhelminth blood fluke Schistosoma mansoni using the xWORM assay technique. Of four compounds tested, two compounds-luteolin (3) and (3R,6R)-linalool oxide acetate (1)-showed dual anthelmintic activity against S. mansoni (IC50 range = 5.8-36.9 ?g/mL) and T. muris (IC50 range = 9.7-20.4 ?g/mL). Using scanning electron microscopy, we determined luteolin as the most efficacious compound against both parasites and additionally was found effective against the schistosomula, the infective stage of S. mansoni (IC50 = 13.3 ?g/mL). Luteolin induced tegumental damage to S. mansoni and affected the cuticle, bacillary bands and bacillary glands of T. muris. Our in vivo assessment of luteolin (3) against T. muris infection at a single oral dosing of 100 mg/kg, despite being significantly (27.6%) better than the untreated control group, was markedly weaker than mebendazole (93.1%) in reducing the worm burden in mice. CONCLUSIONS/SIGNIFICANCE:Among the four compounds tested, luteolin demonstrated the best broad-spectrum activity against two different helminths-T. muris and S. mansoni-and was effective against juvenile schistosomes, the stage that is refractory to the current gold standard drug, praziquantel. Medicinal chemistry optimisation including cytotoxicity analysis, analogue development and structure-activity relationship studies are warranted and could lead to the identification of more potent chemical entities for the control of parasitic helminths of humans and animals.

Project description:BackgroundTwo platyhelminths of biomedical and commercial significance are Schistosoma mansoni (blood fluke) and Fasciola hepatica (liver fluke). These related trematodes are responsible for the chronic neglected tropical diseases schistosomiasis and fascioliasis, respectively. As no vaccine is currently available for anti-flukicidal immunoprophylaxis, current treatment is mediated by mono-chemical chemotherapy in the form of mass drug administration (MDA) (praziquantel for schistosomiasis) or drenching (triclabendazole for fascioliasis) programmes. This overreliance on single chemotherapeutic classes has dramatically limited the number of novel chemical entities entering anthelmintic drug discovery pipelines, raising significant concerns for the future of sustainable blood and liver fluke control.Methodology/ principle findingsHere we demonstrate that 7-keto-sempervirol, a diterpenoid isolated from Lycium chinense, has dual anthelmintic activity against related S. mansoni and F. hepatica trematodes. Using a microtiter plate-based helminth fluorescent bioassay (HFB), this activity is specific (Therapeutic index = 4.2, when compared to HepG2 cell lines) and moderately potent (LD50 = 19.1 ?M) against S. mansoni schistosomula cultured in vitro. This anti-schistosomula effect translates into activity against both adult male and female schistosomes cultured in vitro where 7-keto-sempervirol negatively affects motility/behaviour, surface architecture (inducing tegumental holes, tubercle swelling and spine loss/shortening), oviposition rates and egg morphology. As assessed by the HFB and microscopic phenotypic scoring matrices, 7-keto-sempervirol also effectively kills in vitro cultured F. hepatica newly excysted juveniles (NEJs, LD50 = 17.7 ?M). Scanning electron microscopy (SEM) evaluation of adult F. hepatica liver flukes co-cultured in vitro with 7-keto-sempervirol additionally demonstrates phenotypic abnormalities including breaches in tegumental integrity and spine loss.Conclusions/ significance7-keto-sempervirol negatively affects the viability and phenotype of two related pathogenic trematodes responsible for significant human and animal infectious diseases. This plant-derived, natural product is also active against both larval and adult developmental forms. As such, the data collectively indicate that 7-keto-sempervirol is an important starting point for anthelmintic drug development. Medicinal chemistry optimisation of more potent 7-keto-sempervirol analogues could lead to the identification of novel chemical entities useful for future combinatorial or replacement anthelmintic control.

Project description:Schistosomiasis is caused by a trematode of the genus Schistosoma and affects over 200 million people worldwide. The only drug recommended by the World Health Organization for treatment and control of schistosomiasis is praziquantel. Development of new drugs is therefore of great importance. Thiazoles are regarded as privileged structures with a broad spectrum of activities and are potential sources of new drug prototypes, since they can act through interactions with DNA and inhibition of DNA synthesis. In this context, we report the synthesis of a series of thiazole derivatives and their in vitro schistosomicidal activity by testing eight molecules (NJ03-08; NJ11-12) containing thiazole structures. Parameters such as motility and mortality, egg laying, pairing and parasite viability by ATP quantification, which were influenced by these compounds, were evaluated during the assays. Scanning electron microscopy (SEM) was utilized for evaluation of morphological changes in the tegument. Schistosomula and adult worms were treated in vitro with different concentrations (6.25 to 50 ?M) of the thiazoles for up to 5 and 3 days, respectively. After in vitro treatment for five days with 6.25 ?M NJ05 or NJ07 separately, we observed a decrease of 30% in schistosomula viability, whilst treatment with NJ05+NJ07 lead to a reduction of 75% in viability measured by ATP quantitation and propidium iodide labeling. Adult worms' treatment with 50 ?M NJ05, NJ07 or NJ05 + NJ07 showed decreased motility to 30-50% compared with controls. Compound NJ05 was more effective than NJ07, and adult worm viability after three days was reduced to 25% in parasites treated with 50 ?M NJ05, compared with a viability reduction to 40% with 50 ?M NJ07. SEM analysis showed severe alterations in adult worms with formation of bulges and blisters throughout the dorsal region of parasites treated with NJ05 or NJ07. Oviposition was extremely affected by treatment with the NJ series compounds; at concentrations of 25 ?M and 50 ?M, oviposition reached almost zero with NJ05, NJ07 or NJ05 + NJ07 already at day one. Tested genes involved in egg biosynthesis were all confirmed by qPCR as downregulated in females treated with 25 ?M NJ05 for 2 days, with a significant reduction in expression of p14, Tyrosinase 2, p48 and fs800. NJ05, NJ07 or NJ05+NJ07 treatment of HEK293 (human embryonic cell line) and HES (human epithelial cell line) showed EC50 in the range of 18.42 to 145.20 ?M. Overall, our results demonstrate that those molecules are suitable targets for further development into new drugs for schistosomiasis treatment, although progress is needed to lessen the cytotoxic effects on human cells. According to the present study, thiazole derivatives have schistosomicidal activities and may be part of a possible new arsenal of compounds against schistosomiasis.

Dataset Information

Activity of Combinations of Antioxidants and Anthelmintic Drugs against the Adult Stage of Schistosoma mansoni.

Publications

Activity of Combinations of Antioxidants and Anthelmintic Drugs against the Adult Stage of <i>Schistosoma mansoni</i>.

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