Toxicity of cyclosporin A (CsA) against developmental stages of Schistosoma mansoni in mice

Munro, G. H.; McLaren, Diane J.

doi:10.1017/s003118200006008x

Cited by 17 publications

(9 citation statements)

References 7 publications

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“…A large amount of information is available on the toxic effects and doses of the drug to be safely administered to humans. The drug is known to be anti-parasitic at subimmunosuppressive levels (Munro & McLaren, 1990 ;Page et al 1995) and is suggested to mediate it's effects through inhibition of normal parasite cyclophilin function. However, no direct association between the anti-parasitic effects of CsA and parasite cyclophilin has yet been established (Khattab et al 1998 ;McLauchlan et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Effect of cyclosporin A on the survival and ultrastructure of Echinococcus granulosus protoscoleces in vitro

Colebrook

Jones

et al. 2004

Parasitology

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Surgical treatment of human hydatidsosis involves the use of various scolicidal agents to kill infective Echinococcus granulosus protoscoleces that may disseminate into the peritoneal cavity during surgery and potentially re-infect the patient. Currently, no scolicidal agent is completely effective in killing intracystic protoscoleces in humans. Cyclosporin A (CsA) has previously been found to be lethal for E. granulosus protoscoleces in vitro. In this study, we further assessed the effectiveness of CsA as a scolicidal agent by testing the toxic effect of CsA at higher doses over various time-periods. Experiments were performed on activated and unactivated protoscoleces cultured in nutrient medium or sheep hydatid cyst fluid. All activated protoscoleces were killed following culture in 100 microg/ml of CsA for 3 days and 50 or 20 microg/ml for 5 days. The lethal effect of CsA on unactivated protoscoleces varied but reached 100% over 15 days in culture with 100 or 50 microg/ml of CsA. Pulse treatment of protoscoleces with 50, 20 or 10 microg/ml of CsA for 5 min or 72 h killed all parasites by day 10 and day 5 respectively. Untreated protoscoleces remained greater than 95 % viable for the duration of experiments. Changes in protoscolex ultrastructure induced by treatment with 10 microg/ml of CsA over 10 days in in vitro culture was assessed by TEM. Protoscolex alterations observed in treated parasites included an increase in cellular vacuolization, swelling of mitochondria, rounding of cells, damage to the tegument, decrease in glycogen, a breakdown of the extracellular matrix and an increase in lipid globules. The untreated protoscoleces, by comparison, had few changes during the 10-day culture period with the exception of large amounts of extracellular glycogen observed in the protoscoleces at culture days 7 and 10. From these results, CsA is clearly an effective scolicidal agent in vitro that may have potential application as a new therapeutic agent in the treatment of human hydatid disease.

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Section: Discussionmentioning

confidence: 99%

Effect of cyclosporin A on the survival and ultrastructure of Echinococcus granulosus protoscoleces in vitro

Colebrook

Jones

et al. 2004

Parasitology

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“…The observations in this study of the interaction between CsA and immune effector mechanisms employed an experimental heterologous transfer (rabbit to mouse) model which may not reflect the situation within the natural host. With respect to the immune-mediated elevated mortality rate of CsA-treated worms, it has been previously shown that host leucocytes will invade the morphologically compromised tegument of CsA-treated adult worms and this has been interpreted as the probable causal event in parasite elimination (Munro & McLaren 1990b).…”

Section: Discussionmentioning

confidence: 99%

Synergistic action of cyclosporin A and polyspecific rabbit anti‐sera against murine Schistosoma mansoni

Millership

Chappell

Fallon

1996

Parasite Immunology

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The efficacy of cyclosporin A (CsA) treatment against Schistosoma mansoni in mice was compared with treatments that included co-administration of one of two anti-sera (infected rabbit serum (IRS) obtained by repeated infection and a worm membrane antigen anti-serum (WSS) obtained by immunization with worm surface supernatants). These two sera recognized a number of worm antigens but differed in precise detail. Administration of CsA alone to mice harbouring mature infections of S. mansoni reduced worm burdens and preferentially targeted female worms. Sera administered alone had no effect on worm burdens. Co-administration of worm membrane antigen anti-serum (WSS) with CsA reduced worm burden significantly compared with drug treatment alone. Male worms were more susceptible to this combined treatment regime. Anti-infection serum (IRS) had a lesser stimulatory activity in combination with CsA which was not statistically different from the effects of CsA alone on worm burdens. The data suggest that CsA-induced surface damage to the parasite may reveal specific antigens that were previously unavailable for host attack.

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“…An anti-schistosome effect of cyclosporin A (CsA) was first reported by Bueding et al (1981), and verified in subsequent studies (Bout et al, 1984;Kasinathan et al, 2011;Munro and McLaren, 1990). …”

Section: Chapter 5 -Conclusion and Future Directionsmentioning

confidence: 78%

“…However, the exact mechanism is still unknown and there have been various speculations on how CsA affects schistosomes (Bout et al, 1984;Guorlay et al, 2007;Kasinathan et al, 2011;Munro and McLaren, 1990), with the P-glycoprotein (P-gp) (an ATP-binding cassette (ABC) transporter) (Kasinathan et al, 2011) (2011), I showed that CsA disrupted egg production in schistosomes. Furthermore, I also found that worms treated with CsA also produce eggs that show delay in development and maturation.…”

Section: Discussionmentioning

confidence: 99%

Haem Biosynthesis and Uptake in Schistosoma mansoni

Toh¹

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Schistosomiasis is a major public health problem in many developing countries. The disease is endemic in 74 countries and infects nearly 250 million people worldwide. Among the five main species affecting humans, Schistosoma mansoni and S. japonicum are responsible for the majority of hepato-intestinal schistosomiasis. Praziquantel is the only available drug against this chronic debilitating disease and many vaccines are being trialled in the search for an effective control of the disease.Adult schistosomes are dependent on the blood of their definitive host for nutrition. In the process of ingesting and breaking down host erythrocytes, large quantities of haem are released. Despite being a potentially toxic molecule, haem is an essential factor for numerous biological reactions and may also serve as an important source of iron. The molecules involved in the catabolism of red blood cells (RBC) and release of its end-product haem, are potential targets for development of anthelmintic drugs or vaccines. By contrast, knowledge on haem metabolism and the associated uptake in schistosomes is limited and further research may identify potential targets among the molecules involved in haemoglobin breakdown and haem utilization or sequestration.In the first part of this thesis, the de novo haem biosynthetic capability of schistosomes was determined by investigating two enzymes of the eight-enzyme haem biosynthetic pathway, δ-aminolevulinic acid dehydratase (ALAD) and ferrochelatase (FC). The function of the two enzymes was investigated using a combination of three techniques: (1) in silico analysis of protein sequences;(2) complementation assays using mutant E. coli strains defective in haem biosynthesis; (3) enzymatic assays using the recombinant schistosome proteins. While the in silico analysis suggested that these proteins are likely to be active enzymes, complementation and enzymatic assays were unable to verify their function.In the second part of the thesis, it was hypothesized that an adaptive haem uptake mechanism is present in the schistosomes to support their haem needs. This hypothesis was confirmed with a pulsechase experiment using a fluorescent haem analogue, palladium mesoporphyrin IX (Pd-mP). The results of this experiment indicated that the transmembrane uptake of haem in schistosomes is likely to be an active process that is specific to haem. Further, it was demonstrated that Pd-mP is taken up and accumulated in the vitellaria and ovary of females, suggesting that haem uptake and metabolism is an essential biological process that supports reproduction in schistosomes. Further investigation of the underlying mediating this transmembrane transport of haem was presented by targeting this pathway pharmacologically.ii It was demonstrated that cyclosporin A (CsA) inhibits the uptake of Pd-mP, a fluorescent haem analogue, by the ovary of S. mansoni in concentration-dependent manner. Furthermore, it was shown that worms treated with CsA had significant reduction in egg production and the eggs produced ...

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Toxicity of cyclosporin A (CsA) against developmental stages of Schistosoma mansoni in mice

Cited by 17 publications

References 7 publications

Effect of cyclosporin A on the survival and ultrastructure of Echinococcus granulosus protoscoleces in vitro

Effect of cyclosporin A on the survival and ultrastructure of Echinococcus granulosus protoscoleces in vitro

Synergistic action of cyclosporin A and polyspecific rabbit anti‐sera against murine Schistosoma mansoni

Haem Biosynthesis and Uptake in Schistosoma mansoni

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