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Morphological effects and tegumental alterations induced by mefloquine on schistosomula and adult flukes of Schistosoma mansoni

Published online by Cambridge University Press:  09 October 2009

T. MANNECK
Affiliation:
Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, CH-4002 Basel, Switzerland
Y. HAGGENMÜLLER
Affiliation:
Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, CH-4002 Basel, Switzerland
J. KEISER*
Affiliation:
Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, CH-4002 Basel, Switzerland
*
*Corresponding author: Tel: +41 61 284 8218. Fax: +41 61 284 8105. E-mail: jennifer.keiser@unibas.ch

Summary

There is a pressing need to develop novel anti-schistosomal drugs, as current treatment relies largely on praziquantel (PZQ). To further strengthen current evidence of the anti-schistosomal properties of mefloquine (MQ), we studied the temporal effect of this compound in vitro and in vivo, and examined alterations on the tegumental surface of schistosomula and adults of S. mansoni by means of scanning electron microscopy (SEM). Schistosomula and adults were each incubated in vitro using MQ over a wide concentration range (1–100 μg/ml). In addition, mice infected with adult S. mansoni were treated with a single oral dose of 400 mg/kg MQ, and worms were recovered 24, 48, 72, 96 and 120 h following treatment. MQ showed a rapid onset of action on schistosomula in vitro; 100 and 75 μg/ml of MQ killed schistosomula immediately; the minimal lethal and effective concentrations of MQ on schistosomula after 1 h were 25 and 5 μg/ml, respectively. Adult worms incubated with 100 and 10 μg/ml of MQ were dead after 1 h and 24 h of incubation, respectively. A hepatic shift of adult schistosomes was observed in mice already 24 h after treatment, and 120 h following treatment >98% of all worms had translocated to the liver. SEM observations revealed extensive tegumental destruction, including blebbing, shrinking and sloughing, particularly following in vitro incubation and on the tegument of female worms.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2009

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References

REFERENCES

Abdulla, M. H., Lim, K. C., Sajid, M., McKerrow, J. H. and Caffrey, C. R. (2007). Schistosomiasis mansoni: novel chemotherapy using a cysteine protease inhibitor. PLoS Medicine 4, e14.CrossRefGoogle ScholarPubMed
Basch, P. F. (1981). Cultivation of Schistosoma mansoni in vitro. I. Establishment of cultures from cercariae and development until pairing. The Journal of Parasitology 67, 179185.CrossRefGoogle ScholarPubMed
Basch, P. F. and Basch, N. (1982). Schistosoma mansoni: scanning electron microscopy of schistosomula, adults and eggs grown in vitro. Parasitology 85, 333338.CrossRefGoogle ScholarPubMed
Botros, S. S. and Bennett, J. L. (2007). Praziquantel resistance. Expert Opinion on Drug Discovery 2, 3540.CrossRefGoogle ScholarPubMed
Brindley, P. J. and Sher, A. (1987). The chemotherapeutic effect of praziquantel against Schistosoma mansoni is dependent of host antibody response. The Journal of Immunology 139, 215220.CrossRefGoogle ScholarPubMed
Caffrey, C. R. (2007). Chemotherapy of schistosomiasis: present and future. Current Opinion in Chemical Biology 11, 433439.CrossRefGoogle ScholarPubMed
Caffrey, C. R., Williams, D. L., Todd, M. H., Nelson, D. L., Keiser, J. and Utzinger, J. (2009). Chemotherapeutic development strategies for schistosomiasis. In Drug Discovery in Infectious Diseases: from Molecular Targets to Drug Candidates (ed. Selzer, P. M.),pp. 301321. Wiley, Weinheim, Germany.Google Scholar
Cioli, D. and Pica-Mattoccia, L. (2003). Praziquantel. Parasitology Research 90, 39.CrossRefGoogle ScholarPubMed
Crabtree, J. E. and Wilson, R. A. (1980). Schistosoma mansoni: a scanning electron microscope study of the developing schistosomulum. Parasitology 81, 553564.CrossRefGoogle ScholarPubMed
Doenhoff, M. J., Cioli, D. and Utzinger, J. (2008). Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Current Opinion in Infectious Diseases 21, 659667.CrossRefGoogle ScholarPubMed
Dorn, A., Vippagunta, S. R., Matile, H., Jaquet, C., Vennerstrom, J. L. and Ridley, R. G. (1998). An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials. Biochemical Pharmacology 55, 727736.CrossRefGoogle ScholarPubMed
Eagle, H. (1959). Amino acid metabolism in mammalian cell cultures. Science 130, 432437.CrossRefGoogle ScholarPubMed
Gönnert, R. and Andrews, P. (1977). Praziquantel a new broad-spectrum antischistosomal agent. Zeitschrift für Parasitenkunde 52, 129150.CrossRefGoogle Scholar
Gryseels, B., Polman, K., Clerinx, J. and Kestens, L. (2006). Human schistosomiasis. The Lancet 368, 11061118.CrossRefGoogle ScholarPubMed
Gupta, B. C. and Basch, P. F. (1988). Surface maturation in female Schistosoma mansoni, S. mattheei and Schistosomatium douthitti. International Journal for Parasitology 18, 275280.CrossRefGoogle ScholarPubMed
Hockley, D. J. (1973). Ultrastructure of the tegument of Schistosoma. Advances in Parasitology 11, 233305.CrossRefGoogle ScholarPubMed
Hockley, D. J. and McLaren, D. J. (1973). Schistosoma mansoni: changes in the outer membrane of the tegument during development from cercaria to adult worm. International Journal for Parasitology 3, 1325.CrossRefGoogle ScholarPubMed
Hoffmann, K. F. and Strand, M. (1996). Molecular identification of a Schistosoma mansoni tegumental protein with similarity to cytoplasmic dynein light chains. The Journal of Biological Chemistry 271, 2611726123.CrossRefGoogle ScholarPubMed
Hotez, P. J., Molyneux, D. H., Fenwick, A., Ottesen, E., Ehrlich Sachs, S. and Sachs, J. D. (2006). Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tubercolosis, and malaria. PLoS Medicine 3, e102.CrossRefGoogle Scholar
Jiraungkoorskul, W., Sahaphong, S., Sobhon, P., Riengrojpitak, S. and Kangwanrangsan, N. (2005). Effects of praziquantel and artesunate on the tegument of adult Schistosoma mekongi harboured in mice. Parasitology International 54, 177183.CrossRefGoogle ScholarPubMed
Keiser, J., Chollet, J., Xiao, S. H., Mei, J. Y., Jiao, P. Y., Utzinger, J. and Tanner, M. (2009). Mefloquine – an aminoalcohol with promising antischistosomal properties in mice. PLoS Neglected Tropical Diseases 3, e350.CrossRefGoogle ScholarPubMed
Keiser, J. and Utzinger, J. (2007). Advances in the discovery and development of trematocidal drugs. Expert Opinion on Drug Discovery 2, 9–23.CrossRefGoogle ScholarPubMed
King, C. H. and Dangerfield-Cha, M. (2008). The unacknowledged impact of chronic schistosomiasis. Chronic Illness 4, 6579.CrossRefGoogle ScholarPubMed
McLaren, D. J. and Hockley, D. J. (1977). Blood flukes have a double outer membrane. Nature, London 269, 147149.CrossRefGoogle ScholarPubMed
Miller, F. H. Jr., Tulloch, G. S. and Kuntz, R. E. (1972). Scanning electron microscopy of integumental surface of Schistosoma mansoni. The Journal of Parasitology 58, 693698.CrossRefGoogle ScholarPubMed
Neves, R. H., Machado-Silva, J. R., Pelajo-Machado, M., Oliveira, S. A., Coutinho, E. M., Lenzi, H. L. and Gomes, D. C. (2001). Morphological aspects of Schistosoma mansoni adult worms isolated from nourished and undernourished mice: a comparative analysis by confocal laser scanning microscopy. Memórias do Instituto Oswaldo Cruz 96, 10131016.CrossRefGoogle ScholarPubMed
Pica-Mattoccia, L. and Cioli, D. (2004). Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment. International Journal for Parasitology 34, 527533.CrossRefGoogle ScholarPubMed
Ramalho-Pinto, F. J., Gazzinelli, G., Howells, R. E., Mota-Santos, T. A., Figueiredo, E. A. and Pellegrino, J. (1974). Schistosoma mansoni: defined system for stepwise transformation of cercaria to schistosomule in vitro. Experimental Parasitology 36, 360372.CrossRefGoogle ScholarPubMed
Ramirez, B., Bickle, Q., Yousif, F., Fakorede, F., Mouries, M.-A. and Nwaka, S. (2007). Schistosomes: challenges in compound screening. Expert Opinion on Drug Discovery 2, 5361.CrossRefGoogle ScholarPubMed
Ridley, R. G., and Kita, K. (2007). Helminth Drug Initiative. Expert Opinion on Drug Discovery 2, 1.CrossRefGoogle ScholarPubMed
Rogers, S. H., Shannon, W. A. Jr. and Reeder, R. L. (1983). Schistosoma mansoni adults: Uptake and incorporation of epimeric monosaccharides by the tegument. Proceedings of the Oklahoma Academy of Science 63, 1220.Google Scholar
Sayed, A. A., Simeonov, A., Thomas, C. J., Inglese, J., Austin, C. P. and Williams, D. L. (2008). Identification of oxadiazoles as new drug leads for the control of schistosomiasis. Nature Medicine 14, 407412.CrossRefGoogle ScholarPubMed
Shaw, M. K. (1990). Schistosoma mansoni: stage-dependent damage after in vivo treatment with praziquantel. Parasitology 100, 6572.CrossRefGoogle ScholarPubMed
Shaw, M. K. and Erasmus, D. A. (1983). Schistosoma mansoni: Dose-related tegumental surface changes after in vivo treatment with praziquantel. Zeitschrift für Parasitenkunde 69, 7390.CrossRefGoogle ScholarPubMed
Smithers, S. R. and Terry, R. J. (1965). The infection of laboratory hosts with cercariae of Schistosoma mansoni and the recovery of the adult worms. Parasitology 55, 695700.CrossRefGoogle ScholarPubMed
Steinmann, P., Keiser, J., Bos, R., Tanner, M. and Utzinger, J. (2006). Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. The Lancet Infectious Diseases 6, 411425.CrossRefGoogle ScholarPubMed
Sweeney, T. R. (1981). The present status of malaria chemotherapy: mefloquine a novel antimalarial. Medical Research Reviews 1, 181201.CrossRefGoogle ScholarPubMed
Utzinger, J. and Keiser, J. (2004). Schistosomiasis and soil-transmitted helminthiasis: common drugs for treatment and control. Expert Opinion in Pharmacotherapy 5, 263285.CrossRefGoogle ScholarPubMed
Utzinger, J., Xiao, S., Tanner, M. and Keiser, J. (2007). Artemisinins for schistosomiasis and beyond. Current Opinion in Investigational Drugs 8, 105116.Google ScholarPubMed
van der Werf, M. J., de Vlas, S. J., Brooker, S., Looman, C. W. N., Nagelkerke, N. J. D., Habbema, J. D. F. and Engels, D. (2003). Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Tropica 86, 125139.CrossRefGoogle ScholarPubMed
Van Nassauw, L., Toovey, S., Van Op den Bosch, J., Timmermans, J. P. and Vercruysse, J. (2008). Schistosomicidal activity of the antimalarial drug, mefloquine, in Schistosoma mansoni-infected mice. Travel Medicine and Infectious Diseases 6, 253258.CrossRefGoogle ScholarPubMed
World Health Organization (WHO) (2002). Prevention and control of schistosomiasis and soil-transmitted helminthiasis; report of a WHO expert committee, Geneva 2002. WHO Technical Report Series 912, 157.Google Scholar
World Health Organization (WHO) (2004). The Global Burden of Disease: 2004 Update. World Health Organization, Geneva, Switzerland.Google Scholar
Wilson, R. A. and Barnes, P. E. (1974). The tegument of Schistosoma mansoni: observations on the formation, structure and composition of cytoplasmic inclusions in relation to tegument function. Parasitology 68, 239258.CrossRefGoogle ScholarPubMed
Xiao, S. H., Binggui, S., Chollet, J. and Tanner, M. (2000). Tegumental changes in 21-day-old Schistosoma mansoni harboured in mice treated with artemether. Acta Tropica 75, 341348.CrossRefGoogle ScholarPubMed
Xiao, S. H., Collet, J., Utzinger, J., Matile, H., Mei, J. and Tanner, M. (2001). Artemether administered together with haemin damages schistosomes in vitro. Transactions of the Royal Society of Tropical Medicine and Hygiene 95, 6771.Google ScholarPubMed
Xiao, S. H., Friedman, P. A., Catto, B. A. and Webster, L. T. Jr. (1984). Praziquantel-induced vesicle formation in the tegument of male Schistosoma mansoni is calcium dependent. The Journal of Parasitology 70, 177179.CrossRefGoogle ScholarPubMed
Xiao, S., Keiser, J., Chollet, J., Utzinger, J., Dong, Y., Endriss, Y., Vennerstrom, J. L. and Tanner, M. (2007). In vitro and in vivo activities of synthetic trioxoloanes against major human schistosome species. Antimicrobial Agents and Chemotherapy 51, 14401445.CrossRefGoogle ScholarPubMed
Xiao, S. H., Shen, B., Chollet, J., Utzinger, J. and Tanner, M. (2000). Tegumental changes in adult Schistosoma mansoni harbored in mice treated with artemether. The Journal of Parasitology 86, 11251132.Google ScholarPubMed
Xiao, S. H., Yang, Y. Q., Shu, Y. S. and Wang, Z. W. (1981). Ultrastructural changes of the tegument, syncithium, vitelline cells and muscles of Schistosoma japonicum caused by pyquiton. Acta Zoologica Sinica 27, 305309.Google Scholar
Xiao, S. H., Yang, Y. Q., Yang, H. Z., Guo, H. F. and Shao, B. R. (1983). Observation on tegument damage of Schistosoma japonicum and penetration of host leucocytes into the worm body caused by pyquiton. Acta Pharmaceutica Sinica 18, 241246.Google ScholarPubMed
Yolles, T. K., Moore, D. V., De Giusti, D. L., Ripsom, C. A. and Meleney, H. E. (1947). A technique for the perfusion of laboratory animals for the recovery of schistosomes. The Journal of Parasitology 33, 419426.CrossRefGoogle ScholarPubMed
Zhang, C., Xiao, S., Utzinger, J., Chollet, J., Keiser, J. and Tanner, M. (2009). Histopathological changes in adult Schistosoma japonicum harbored in mice treated with a single dose of mefloquine. Parasitology Research 104, 14071416.CrossRefGoogle ScholarPubMed
Zhou, Y. and Podesta, R. B. (1992). Ring-shaped organization of cytoskeletal F-actin associated with surface sensory receptors of Schistosoma mansoni: A confocal and electron microscopic study. Tissue and Cell 24, 3749.CrossRefGoogle ScholarPubMed