Biological and immunological activity of new imidazolidines against adult worms of Schistosoma mansoni

Neves, José Maria Gomes; Botelho, Sandra Paula Sarinho; Melo, Cristiane Moutinho Lagos de; Pereira, Valéria Rêgo Alves; Lima, Maria do Carmo Alves de; Pitta, Ivan da Rocha; Albuquerque, Mônica Camelo Pessôa de Azevedo; Galdino, Suely Lins

doi:10.1007/s00436-010-1886-y

Cited by 28 publications

(15 citation statements)

References 31 publications

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“…Moreover, mefloquine was shown to exhibit a high capacity to induce morphological alteration in the outer membrane of schistosomula and adult schistosomes. Other examples of promising antischistosomal drugs under research include benzothiazole derivatives (Mahran et al 2007), aminoalkanethiols and corresponding disulfides (de Oliveira Penido et al 2008), alkoxyalkyl esters of acyclic nucleoside phosphonates (Botros et al 2009), trioxaquines (Boissier et al 2009), and thioxo-imidazoline compounds (Neves et al 2010(Neves et al , 2011. In addition, modifications in the manner of drug delivery for drugs with poor hydrosolubility have also been investigated to increase antischistosomal efficacy (de Araújo et al 2007).…”

Section: Discussionmentioning

confidence: 98%

Ultrastructural analysis of miltefosine-induced surface membrane damage in adult Schistosoma mansoni BH strain worms

et al. 2012

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Schistosomiasis is an infectious parasitic disease caused by helminths from the genus Schistosoma; it affects over 200 million people globally and is endemic in 70 countries. In Brazil, 6 million individuals are infected with Schistosoma mansoni. Furthermore, as the prevalence of S. mansoni infections is increasing, approximately 26 million citizens in 19 Brazilian states are at risk for infection. Schistosomiasis disease control involves predominately the administration of a single drug, praziquantel. Although praziquantel exhibits chemotherapeutic efficacy and safety, its massive use in endemic zones, the possibility of the emergence of drug-resistant Schistosoma parasites, and the lack of another efficacious antischistosomal drug demand the discovery of new schistosomicidal compounds. First developed as anti-tumor drug, miltefosine is an alkylphospholipid derivative that exhibits bioactivity against Leishmania and Trypanosoma parasites, free-living protozoa, bacteria, and fungi. With its anti-parasite activity, miltefosine was the first orally administered drug against visceral and cutaneous leishmaniasis approved. Previously, by means of the MTT cytotoxic assay and a DNA fragmentation test, we verified that, at doses of 100 and 200 μM (40 and 80 μg/mL), miltefosine exhibited in vitro schistosomicidal activity against adult S. mansoni worms. Here, we present ultrastructural evidence of rapid, severe miltefosine-induced surface membrane damage in S. mansoni following drug treatment. The number of dead parasites was concentration- and time-dependent following miltefosine treatment. At a miltefosine concentration of 200 μM (∼80 μg/mL), in vitro parasite killing was initiated as early as 3 h post-incubation, and it was maximal after 24 h of treatment. The parasite death was preceded by progressive surface membrane damage, characterized by tegument peeling, spine reduction and erosion, blister formation and rupture, and the emergence of holes. According to our present results, miltefosine is very effective at inducing membrane destruction of S. mansoni with a short onset of pharmacological action.

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Section: Discussionmentioning

confidence: 98%

Ultrastructural analysis of miltefosine-induced surface membrane damage in adult Schistosoma mansoni BH strain worms

et al. 2012

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“…The production of NO may also contribute to worm mortality by way of S-nitrosylation of cysteine proteases, given that schistosomes express cysteine proteases that play a role in digestion, reproduction, and protein turnover and that this appears to be a common and widespread mechanism (58,62). Studies have also shown that compounds that induce the NO release possess potential immunomodulatory properties (63)(64)(65). The present study found that LpQM-14 stimulated NO production for the three incubation times analyzed, while LpQM-45 stimulated production only after 48 h of exposure.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Anti-Schistosoma mansoni Activity of Thiosemicarbazones and Thiazoles

Santiago

Oliveira

Filho

et al. 2014

Antimicrob Agents Chemother

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f Schistosomiasis is a chronic and debilitating disease caused by a trematode of the genus Schistosoma and affects over 207 million people. Chemotherapy is the only immediate recourse for minimizing the prevalence of this disease and involves predominately the administration of a single drug, praziquantel (PZQ). Although PZQ has proven efficacy, there is a recognized need to develop new drugs as schistosomicides since studies have shown that repeated use of this drug in areas of endemicity may cause a temporary reduction in susceptibility in isolates of Schistosoma mansoni. Hydrazones, thiosemicarbazones, phthalimides, and thiazoles are thus regarded as privileged structures used for a broad spectrum of activities and are potential candidates for sources of new drug prototypes. The present study determined the in vitro schistosomicidal activity of 10 molecules containing these structures. During the assays, parameters such motility and mortality, oviposition, morphological changes in the tegument, cytotoxicity, and immunomodulatory activity caused by these compounds were evaluated. The results showed that compounds formed of thiazole and phthalimide led to higher mortality of worms, with a significant decline in motility, inhibition of pairing and oviposition, and a mortality rate of 100% starting from 144 h of exposure. These compounds also stimulated the production of nitric oxide and tumor necrosis factor alpha (TNF-␣), thereby demonstrating the presence of immunomodulatory activity. The phthalyl thiazole LpQM-45 caused significant ultrastructural alterations, with destruction of the tegument in both male and female worms. According to the present study, phthalyl thiazole compounds possess antischistosomal activities and should form the basis for future experimental and clinical trials.

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“…As previously noted, there was no structural alteration of the spines and tubercles on the surface of the parasites caused by incubation with LDL, compared with studies involving drugs administration such as praziquantel and artemether that cause swelling, erosion, peeling, vesiculation, and collapse of tegumental ridges (Shuhua et al 2002;Neves et al 2010). Long-term LDL incubations (120 min) caused a decrease of approximately 30% of the original particles' size in the beginning of the experiments.…”

Section: Discussionmentioning

confidence: 76%

Scanning electron microscopy of the human low-density lipoprotein interaction with the tegument of Schistosoma mansoni

et al. 2011

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The interaction between host molecules and Schistosoma mansoni has been regarded as a key feature for parasite survival. In this work, scanning electron microscopy was used to study the interaction of human low-density lipoprotein (LDL) with the tegument of the adult worm of S. mansoni. Worms were incubated in RPMI 1640 containing 10% of LPDS and 40 μg LDL/mL during 30, 60, and 120 min. Control worms were processed in the same way, without LDL. After the incubations, the samples were fixed and processed to scanning electron microscopy. The results demonstrated interaction of the LDL particles with the male parasite tegument. Male and female worms incubated without LDL from 0 (control) to 120 min did not show alterations in the tegument. It was observed a larger number of LDL particles on the dorsal region of male adult worm than others regions (anterior, posterior and gynecophoral canal). The female tegument did not show adherence of LDL. Aggregates on the tegument of the male worm were in greater number and size in the incubation times of 30 and 60 min than 120 min. The comparison between 30 and 120 min of incubation showed that the particles' size diminished from 2,650-860 nm to 634-363 nm, respectively. Such reduction can be due to the capture and the use of the lipids by the worm. Therefore, the internalization of lipids from LDL by the male worms seems to be a mechanism independent of endocytosis. Differences between males and females suggest lipid transference from male to female through gynecophoral canal.

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Biological and immunological activity of new imidazolidines against adult worms of Schistosoma mansoni

Cited by 28 publications

References 31 publications

Ultrastructural analysis of miltefosine-induced surface membrane damage in adult Schistosoma mansoni BH strain worms

Ultrastructural analysis of miltefosine-induced surface membrane damage in adult Schistosoma mansoni BH strain worms

Evaluation of the Anti-Schistosoma mansoni Activity of Thiosemicarbazones and Thiazoles

Scanning electron microscopy of the human low-density lipoprotein interaction with the tegument of Schistosoma mansoni

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