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Adult triclabendazole-resistant Fasciola hepatica: morphological changes in the tegument and gut following in vivo treatment with artemether in the rat model

Published online by Cambridge University Press:  01 June 2009

J.F. O'Neill ,
R.C. Johnston ,
L. Halferty ,
G.P. Brennan ,
J. Keiser  and
I. Fairweather
J.F. O'Neill
Affiliation:
Parasite Proteomics and Therapeutics research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast, Northern IrelandBT9 7BL
R.C. Johnston
Affiliation:
Parasite Proteomics and Therapeutics research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast, Northern IrelandBT9 7BL
L. Halferty
Affiliation:
Parasite Proteomics and Therapeutics research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast, Northern IrelandBT9 7BL
G.P. Brennan
Affiliation:
Parasite Proteomics and Therapeutics research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast, Northern IrelandBT9 7BL
J. Keiser
Affiliation:
Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, PO Box, CH–4002Basel, Switzerland
I. Fairweather*
Affiliation:
Parasite Proteomics and Therapeutics research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast, Northern IrelandBT9 7BL
*
*Fax:+44 28 90975877 E-mail: i.fairweather@qub.ac.uk
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Abstract

A study has been carried out to determine the morphological changes to the adult liver fluke, Fasciola hepatica after treatment in vivo with artemether. Rats were infected with the triclabendazole-resistant Sligo isolate of F. hepatica, dosed orally with artemether at a concentration of 200 mg/kg and flukes recovered at 24, 48 and 72 h post-treatment (p.t.). Surface changes were monitored by scanning electron microscopy and fine structural changes to the tegument and gut by transmission electron microscopy. Twenty-four hours p.t., the external surface showed minor disruption, in the form of mild swelling of the tegument. The tegumental syncytium and sub-tegumental tissues appeared relatively normal. Forty-eight and seventy-two hours p.t., disruption to the tegumental system increased, with isolated patches of surface blebbing and reduced production of secretory bodies by the tegumental cells being the main changes seen. The gastrodermal cells showed a relatively normal morphology 24 h p.t. By 48 h, large numbers of autophagic vacuoles and lipid droplets were present. Autophagy increased in magnitude by 72 h p.t. and substantial disruption to the granular endoplasmic reticulum was observed. Results from this study show that flukes treated in vivo with artemether display progressive and time-dependent alterations to the tegument and gut. Disruption to the gut was consistently and substantially more severe than that to the tegument, suggesting that an oral route of uptake for this compound predominates. This is the first study providing ultrastructural information on the effect of an artemisinin compound against liver fluke.

Type
Research Papers
Information
Journal of Helminthology , Volume 83 , Special Issue 2: Symposium and related papers from the 10th European Multicolloquium of Parasitology , June 2009 , pp. 151 - 163
Copyright
Copyright © Cambridge University Press 2009

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References

Álvarez-Sánchez, M.A., Mainar-Jaime, R.C., Pérez-García, J. & Rojo-Vázquez, F.A. (2006) Resistance of Fasciola hepatica to triclabendazole and albendazole in sheep in Spain. Veterinary Record 159, 424–425.CrossRefGoogle ScholarPubMed
Bennett, C.E. (1975) Scanning electron microscopy of Fasciola hepatica during migration in the mouse. Journal of Parasitology 61, 892–898.CrossRefGoogle Scholar
Berman, P.A. & Adams, P.A. (1997) Artemisinin enhances heme-catalysed oxidation of lipid membranes. Free Radical Biology and Medicine 22, 1283–1288.CrossRefGoogle ScholarPubMed
Boray, J.C. (1994) Disease of domestic animals caused by flukes. 49 pp. Rome, Food and Agricultural Organization of the United Nations.Google Scholar
Boray, J.C., Crowfoot, P.D., Strong, M.B., Allison, J.R., Schellenbaum, M., Von Orelli, M. & Sarasin, G. (1983) Treatment of immature and mature Fasciola hepatica infections in sheep with triclabendazole. Veterinary Record 113, 315–317.CrossRefGoogle ScholarPubMed
Coles, G.C. & Stafford, K.A. (2001) Activity of oxyclozanide, nitroxynil, clorsulon and albendazole against adult triclabendazole-resistant Fasciola hepatica. Veterinary Record 148, 723–724.CrossRefGoogle ScholarPubMed
Coles, G.C., Rhodes, A.C. & Stafford, K.A. (2000) The activity of closantel against adult triclabendazole-resistant Fasciola hepatica. Veterinary Record 146, 504.CrossRefGoogle ScholarPubMed
Dubin, M. & Stoppani, A.O.M. (2000) Programmed cell death and apoptosis. The role of mitochondria. Medicina-Buenosa Aires 60, 375–386.Google ScholarPubMed
Eckstein-Ludwig, U., Webb, R., van Goethem, I., East, J., Lee, A., Kimura, M., O'Neill, P., Bray, P., Ward, S. & Krishna, S. (2003) Artemisinins target the SERCA of Plasmodium falciparum. Nature 424, 957–961.CrossRefGoogle ScholarPubMed
Fairweather, I. (2005) Triclabendazole: new skills to unravel an old(ish) enigma. Journal of Helminthology 79, 227–234.CrossRefGoogle ScholarPubMed
Fairweather, I. (2009) Triclabendazole progress report, 2005–2009: an advancement of learning? Journal of Helminthology.CrossRefGoogle ScholarPubMed
Fairweather, I., Threadgold, L.T. & Hanna, R.E.B. (1999) Development of Fasciola hepatica in the mammalian host. pp. 47–111in Dalton, J.P. (Ed.) Fasciolosis. Wallingford, Oxon, CAB International.Google Scholar
Halferty, L., Brennan, G.P., Hanna, R.E.B., Edgar, H.W., Meaney, M., McConville, M., Trudgett, A., Hoey, L. & Fairweather, I. (2008) Tegumental surface changes in juvenile Fasciola hepatica in response to treatment in vivo with triclabendazole. Veterinary Parasitology 155, 49–58.CrossRefGoogle ScholarPubMed
Hien, T.T., Truong, N.G., Minh, N.H., Dat, H.D., Dung, N.T., Hue, N.T., Dung, T.K., Tuan, P.Q., Campbell, J.I., Farrar, J.J. & Day, J.N. (2008) A randomised controlled pilot study of artesunate versus triclabendazole for human fascioliasis in Central Vietnam. American Journal of Tropical Medicine and Hygiene 78, 388–392.CrossRefGoogle ScholarPubMed
Jung, J., Kim, H., Nam, K.Y. & No, K.T. (2005) Three-dimensional structure of Plasmodium falciparum Ca-ATPase (PfATP6) and docking of artemisinin derivatives to PfATP6. Bioorganic and Medicinal Chemistry Letters 15, 2994–2997.CrossRefGoogle Scholar
Keiser, J. & Utzinger, J. (2007) Artemisinins and synthetic trioxolanes in the treatment of helminth infections. Current Opinion in Infectious Diseases 20, 605–612.CrossRefGoogle ScholarPubMed
Keiser, J. & Morson, G. (2008a) Fasciola hepatica: tegumental alterations in adult flukes following in vitro and in vivo administration of artesunate and artemether. Experimental Parasitology 118, 228–237.CrossRefGoogle ScholarPubMed
Keiser, J. & Morson, G. (2008b) Fasciola hepatica: surface tegumental responses to in vitro and in vivo treatment with the experimental fasciolicide OZ78. Experimental Parasitology 119, 87–93.CrossRefGoogle ScholarPubMed
Keiser, J., Engels, D., Büscher, G. & Utzinger, J. (2005) Triclabendazole for the treatment of fascioliasis and paragonimiasis. Expert Opinion in Investigational Drugs 14, 1513–1526.CrossRefGoogle ScholarPubMed
Keiser, J., Xiao, S.H., Xue, J., Chang, Z.S., Odermatt, P., Tesana, S., Tanner, M. & Utzinger, J. (2006a) Effect of artesunate and artemether against Clonorchis sinensis and Opisthorchis viverrini in rodent models. International Journal of Antimicrobial Agents 28, 370–373.CrossRefGoogle ScholarPubMed
Keiser, J., Xiao, S.H., Tanner, M. & Utzinger, J. (2006b) Artesunate and artemether are effective fasciolicides in the rat model and in vitro. Journal of Antimicrobial Chemotherapy 57, 1139–1145.CrossRefGoogle ScholarPubMed
Keiser, J., Utzinger, J., Tanner, M., Dong, Y. & Vennerstrom, J.L. (2006c) The synthetic peroxide OZ78 is effective against Echinostoma caproni and Fasciola hepatica. Journal of Antimicrobial Chemotherapy 58, 1193–1197.CrossRefGoogle ScholarPubMed
Keiser, J., Utzinger, J., Vennerstrom, J.L., Dong, Y., Brennan, G. & Fairweather, I. (2007a) Activity of artemether and OZ78 against triclabendazole-resistant Fasciola hepatica. Transactions of the Royal Society for Tropical Medicine and Hygiene 101, 1219–1222.CrossRefGoogle ScholarPubMed
Keiser, J., Xiao, S.H., Dong, Y., Utzinger, J. & Vennerstrom, J.L. (2007b) Clonorchicidal properties of the synthetic trioxolane OZ78. Journal of Parasitology 93, 1209–1214.CrossRefGoogle ScholarPubMed
Keiser, J., Rinaldi, L., Veneziano, V., Mezzino, L., Tanner, M., Utzinger, J. & Cringoli, G. (2008) Efficacy and safety of artemether against a natural Fasciola hepatica infection in sheep. Parasitology Research 103, 517–522.CrossRefGoogle ScholarPubMed
Lefèvre, G. & Thomsen, M.S. (1999) Clinical pharmacokinetics of artemether and lumefantrine (Riamet®). Clinical Drug Investigation 18, 467–480.CrossRefGoogle Scholar
Li, Q.-G., Peggins, J.O., Fleckenstein, L.L., Masonic, K., Heiffer, M.H. & Brewer, T.G. (1998) The pharmacokinetics and bioavailability of dihydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats. Journal of Pharmacy and Pharmacology 50, 173–182.CrossRefGoogle ScholarPubMed
Li, W., Mo, W., Shen, D., Sun, L., Wang, J., Lu, S., Gitschier, J.M. & Zhou, B. (2005) Yeast model uncovers dual roles of mitochondria in the action of artemisinin. PloS Genetics 1, 329–334.CrossRefGoogle ScholarPubMed
Mas-Coma, S., Bargues, M.D. & Valero, M.A. (2005) Fascioliasis and other plant-borne trematode zoonoses. International Journal for Parasitology 35, 1255–1278.CrossRefGoogle ScholarPubMed
Mason, R.P., Walter, M.F. & Mason, P.E. (1997) Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. Free Radical Biology and Medicine 23, 419–425.CrossRefGoogle ScholarPubMed
McConville, M., Brennan, G.P., Flanagan, A., Edgar, H.W.J., McCoy, M., Castillo, R., Hernández-Campos, A. & Fairweather, I. (2008) Surface and internal tegumental changes in juvenile Fasciola hepatica following treatment in vivo with the experimental fasciolicide, compound alpha. Veterinary Parasitology 153, 52–64.CrossRefGoogle ScholarPubMed
McConville, M., Brennan, G.P., Flanagan, A., Edgar, H.W.J., Hanna, R.E.B., McCoy, M., Gordon, A.W., Castillo, R.C., Hernández-Campos, A. & Fairweather, I. (2009a) An evaluation of the efficacy of compound alpha and triclabendazole against two isolates of Fasciola hepatica. Veterinary Parasitology (in press).CrossRefGoogle ScholarPubMed
McConville, M., Brennan, G.P., Flanagan, A., Edgar, H.W.J., Castillo, R., Hernández-Campos, A. & Fairweather, I. (2009b) Ultrastructural changes to the tegumental system and the gastrodermal cells in mature flukes following in vivo treatment with the experimental fasciolicide, compound alpha. Parasitology (in press).Google Scholar
McCoy, M.A., Fairweather, I., Brennan, G.P., Kenny, J.M. & Forbes, A.B. (2005) The efficacy of nitroxynil and triclabendazole administered synchronously against juvenile triclabendazole-resistant Fasciola hepatica in sheep. Research in Veterinary Sciences 78, 33.Google Scholar
McKinstry, B., Fairweather, I., Brennan, G.P. & Forbes, A.B. (2003) Fasciola hepatica: tegumental surface alterations following treatment in vivo and in vitro with nitroxynil (Trodax). Parasitology Research 91, 251–263.CrossRefGoogle ScholarPubMed
McKinstry, B., Brennan, G.P., Halferty, L., Forbes, A.B. & Fairweather, I. (2007) Ultrastructural changes induced in the tegument and gut of Fasciola hepatica following in vivo and in vitro drug treatment with nitroxynil (Trodax). Parasitology Research 101, 929–941.CrossRefGoogle ScholarPubMed
McKinstry, B., Halferty, L., Brennan, G.P. & Fairweather, I. (2009) Morphological response of triclabendazole-susceptible and triclabendazole-resistant isolates of Fasciola hepatica to treatment in vitro with nitroxynil (Trodax). Parasitology Research 104, 645–655.CrossRefGoogle ScholarPubMed
Meaney, M., Fairweather, I., Brennan, G.P., McDowell, L.S.L. & Forbes, A.B. (2003) Fasciola hepatica: effects of the fasciolicide clorsulon in vitro and in vivo on the tegumental surface, and a comparison of the effects on young- and old-mature flukes. Parasitology Research 91, 238–250.CrossRefGoogle Scholar
Meaney, M., Haughey, S., Brennan, G.P. & Fairweather, I. (2005a) A scanning electron microscope study on the route of entry of clorsulon into the liver fluke, Fasciola hepatica. Parasitology Research 95, 117–128.CrossRefGoogle Scholar
Meaney, M., Haughey, S., Brennan, G.P. & Fairweather, I. (2005b) A scanning electron microscope study on the route of entry of clorsulon into the liver fluke, Fasciola hepatica. Parasitology Research 96, 189–198.CrossRefGoogle Scholar
Meaney, M., Haughey, S., Brennan, G.P. & Fairweather, I. (2005c) Ultrastructural observations on oral ingestion and trans-tegumental uptake of clorsulon by the liver fluke, Fasciola hepatica. Parasitology Research 95, 201–212.CrossRefGoogle ScholarPubMed
Meaney, M., Allister, J., McKinstry, B., McLaughlin, K., Brennan, G.P., Forbes, A.B. & Fairweather, I. (2006) Fasciola hepatica: morphological effects of a combination of triclabendazole and clorsulon against mature fluke. Parasitology Research 99, 609–621.CrossRefGoogle ScholarPubMed
Mitchell, G.B.B. (2002) Update on fasciolosis in cattle and sheep. In Practice 24, 378–385.CrossRefGoogle Scholar
Mottier, L., Alvarez, L., Fairweather, I. & Lanusse, C. (2006a) Resistance-induced changes in triclabendazole transport in Fasciola hepatica: ivermectin reversal effect. Journal of Parasitology 92, 1355–1360.CrossRefGoogle ScholarPubMed
Mottier, L., Alvarez, L., Ceballos, L. & Lanusse, C. (2006b) Drug transport mechanisms in helminth parasites: passive diffusion of benzimidazole anthelmintics. Experimental Parasitology 113, 49–57.CrossRefGoogle ScholarPubMed
Navaratnam, V., Mansor, S.M., Sit, N.W., Grace, J., Li, Q. & Olliaro, P. (2000) Pharmacokinetics of artemisinin-type compounds. Clinical Pharmacokinetics 39, 255–266.CrossRefGoogle ScholarPubMed
Overend, D.J. & Bowen, F.L. (1995) Resistance of Fasciola hepatica to triclabendazole. Australian Veterinary Journal 72, 275–276.CrossRefGoogle ScholarPubMed
Robinson, G. & Threadgold, L.T. (1975) Electron microscope studies of Fasciola hepatica. XII. The fine structure of the gastrodermis. Experimental Parasitology 37, 20–36.CrossRefGoogle ScholarPubMed
Robinson, M.W., Trudgett, A., Hoey, E.M. & Fairweather, I. (2002) Triclabendazole-resistant Fasciola hepatica: β-tubulin and response to in vitro treatment with triclabendazole. Parasitology 124, 325–338.CrossRefGoogle ScholarPubMed
Rohn, T.R., Hinds, T.R. & Vincenzi, F.F. (1996) Inhibition of Ca2+-pump ATPase and the Na+/K+-pump ATPase by iron-generated free radicals. Protection by 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrol0[2,3-d]pyrimidine sulfate (U-89843D), a potent, novel, antioxidant/free radical scavenger. Biochemical Pharmacology 51, 471–476.CrossRefGoogle Scholar
Skuce, P.J. & Fairweather, I. (1990) The effect of the hydrogen ionophore closantel upon the pharmacology and ultrastructure of the adult liver fluke Fasciola hepatica. Parasitology Research 76, 241–250.CrossRefGoogle ScholarPubMed
Sumegi, B., Kovacs, K., Veres, B., Radnai, B., Varbiro, G., Bognar, Z., Toth, A. & Gallyas, F. (2005) Oxidative stress and the endoplasmic reticulum. pp. 121–130in Benedetti, A., Banhegyi, G. & Burchell, A. (Eds) Endoplasmic reticulum: a metabolic compartment (NATO Science Series, Vol. 363). Amsterdam, IOS Press.Google Scholar
Threadgold, L.T. (1963) The tegument and associated structures of Fasciola hepatica. Quarterly Journal of the Microscopical Society 104, 505–512.Google Scholar
Threadgold, L.T. (1967) Electron-microscope studies of Fasciola hepatica. III. Further observations on the tegument and associated structures. Parasitology 57, 633–637.CrossRefGoogle Scholar
Toner, E., McConvery, F., Brennan, G.P., Meaney, M. & Fairweather, I. (2009) A scanning electron microscope study on the route of entry of triclabendazole into the liver fluke, Fasciola hepatica. Parasitology (in press).CrossRefGoogle Scholar
Uhlemann, A.-C., Wittlin, S., Matile, H., Bustamante, L.Y. & Krishna, S. (2007) Mechanism of antimalarial action of the synthetic trioxolane RBX1160 (OZ277). Antimicrobial Agents and Chemotherapy 51, 667–672.CrossRefGoogle ScholarPubMed
Utzinger, J., Xiao, S.-H., Tanner, M. & Keiser, J. (2007) Artemisinins for schistosomiasis and beyond. Current Opinion in Investigational Drugs 8, 105–116.Google ScholarPubMed
Wakabayashi, T. & Karbowski, M. (2001) Structural changes of mitochondria related to apoptosis. Biological Signals and Receptors 10, 26–56.CrossRefGoogle ScholarPubMed
Walker, S., McKinstry, B., Boray, J.C., Brennan, G.P., Trudgett, A., Hoey, E.M., Fletcher, H. & Fairweather, I. (2004) Response of two isolates of Fasciola hepatica to treatment with triclabendazole in vivo and in vitro. Parasitology Research 94, 427–438.CrossRefGoogle ScholarPubMed
WHO (2007) Report of the WHO Informal Meeting on use of triclabendazole in fascioliasis control, held at WHO Headquarters, Geneva, Switzerland, October 2006. 33 pp.Google Scholar
Wolstenholme, A., Fairweather, I., Prichard, R., Von Samson-Himmelstjerna, G. & Sangster, N. (2004) Drug resistance in veterinary helminths. Trends in Parasitology 20, 469–476.CrossRefGoogle ScholarPubMed
Woodrow, C., Haynes, R. & Krishna, S. (2005) Artemisinins. Postgraduate Medical Journal 81, 71–78.CrossRefGoogle ScholarPubMed
Xiao, S.-H., Wu, Y.-L., Tanner, M., Wu, W.-M., Utzinger, J., Mei, J.-Y., Scorneaux, B., Chollet, J. & Zhai, Z. (2003) Schistosoma japonicum: in vitro effects of artemether combined with haemin depend on cultivation media and appraisal of artemether products appearing in the media. Parasitology Research 89, 459–466.CrossRefGoogle ScholarPubMed