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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Jatropha elliptica is a shrub distributed throughout the north and west of Brazil and reputedly possesses a wide range of therapeutical properties. The roots of this plant possess molluscicidal activity and contain terpenoids, coumarin, lignoid, steroids and alkaloid. In the present study, we assessed the schistosomicidal, miracicidal and cercaricidal activities (against Schistosoma mansoni) and molluscicidal activities (against adults and egg masses of Biomphalaria glabrata) of the alkaloid diethyl 4-phenyl-2,6-dimethyl-3,5-pyridinedicarboxylate, isolated from the ethanol extract of the rhizome of J. elliptica, have been determined. The alkaloid was 100 % lethal to adult schistosomes within 4 days at a concentration of 50 μg/mL. Alterations were observed in the schistosome tegument occasioned by treatment with the alkaloid, such as formation of vesicles and vacuolisation. The extent of tegumental damage of the worm was proportional to the time of incubation and to the concentration of compound. The alkaloid also exhibited a potent cercaricidal activity (LC100 = 2 μg/mL); it was totally ineffective against miracicidal forms of the parasite. Moreover, the alkaloid presented strong activity against adult snails (LC90 = 36.43 μg/mL) but was inactive against their egg masses. It is observed then the potential of this compound for the development of new therapies for the treatment of schistosomiasis.

Adult worm extract from Ascaris suum (Asc) has immunosuppressive activity and elicits Th2/IL-4/IL-10 response. This study evaluated the prophylactic and therapeutic effect of Asc in a murine model of concanavalin A (ConA)-induced autoimmune hepatitis (AIH). BALB/c mice received ConA, iv, (20 mg/kg), and three groups of animals were formed: (1) AIH, received only ConA; (2) AIH + Asc prophylactic, treated with Asc (1 mg/ml), ip, 30 min before of the AIH; and (3) AIH + Asc therapeutic, treated with Asc 2 h after the AIH. Plasma transaminase and immunoglobulins (measured at 8 and 24 h and 7 days after treatment) and cytokine production (IL-4, IL-10, IL-13, and IFN-γ) by splenocytes upon ConA and Asc stimulus were compared. The livers were weighed and examined histologically. In the AIH group, there was an increase in liver weight, transaminase levels, and total immunoglobulins. These parameters were reduced by 8-24 h and 7 days in the prophylactic group, but in the therapeutic group, only on day 7. The survival rate of mice in the AIH group was 38.5%, compared to 67% in the therapeutic Asc group. The survival rate of the animals with AIH that were prophylactically treated with Asc was 100%. A decrease of cellular infiltration and high levels of IL-4, IL-10, and IL-13 were induced by Asc. An increase of liver fibrosis was also observed, but with less intensity with prophylactic treatment. Thus, the Ascaris components have an inhibitory effect on AIH, with an intense Th2 immune response.

The only drug available for treating schistosomiasis is praziquantel, however there are already reports of resistance to its use in treatment, making it necessary to search and develop new compounds to combat schistosomiasis. We tested, in vitro, two new products, Laboratório de Planejamento de Síntese de Fármacos (LPSF)/5-(4-chloro-benzylidene-3-(4-nitrebenzyl)-4-thioxo-imidazolidin-2-one (RZS-2) and LPSF/5-(4-fluoride-benzylidene-3-(4-nitrebenzyl)-4-thioxo-imidazolidin-2-one (RZS-5) imidazolidines, against adult worms of Schistosoma mansoni. Efficacy and safety of these compounds were analyzed through IC50 cytotoxicity, immune response and cell viability tests. At different concentrations ranging from 40-640 microM, the imidazolidines produced motor abnormalities, inhibition of pairing and oviposition and mortality within 24 h at the higher concentrations. Although not triggering changes in IFN-gamma and IL-10, LPSF/RZS-2 and LPSF/RZS-5 induced production of nitric oxide and showed similar behavior to praziquantel in the cell death test.

Schistosoma mansoni antigens in the early life alter homologous and heterologous immunity during postnatal infections. We evaluate the immunity to parasite antigens and ovalbumin (OA) in adult mice born/suckled by schistosomotic mothers. Newborns were divided into: born (BIM), suckled (SIM) or born/suckled (BSIM) in schistosomotic mothers, and animals from noninfected mothers (control). When adults, the mice were infected and compared the hepatic granuloma size and cellularity. Some animals were OA + adjuvant immunised. We evaluated hypersensitivity reactions (HR), antibodies levels (IgG1/IgG2a) anti-soluble egg antigen and anti-soluble worm antigen preparation, and anti-OA, cytokine production, and CD4+FoxP3+T-cells by splenocytes. Compared to control group, BIM mice showed a greater quantity of granulomas and collagen deposition, whereas SIM and BSIM presented smaller granulomas. BSIM group exhibited the lowest levels of anti-parasite antibodies. For anti-OA immunity, immediate HR was suppressed in all groups, with greater intensity in SIM mice accompanied of the remarkable level of basal CD4+FoxP3+T-cells. BIM and SIM groups produced less interleukin (IL)-4 and interferon (IFN)-g. In BSIM, there was higher production of IL-10 and IFN-g, but lower levels of IL-4 and CD4+FoxP3+T-cells. Thus, pregnancy in schistosomotic mothers intensified hepatic fibrosis, whereas breastfeeding diminished granulomas in descendants. Separately, pregnancy and breastfeeding could suppress heterologous immunity; however, when combined, the responses could be partially restored in infected descendants.

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