Surface and internal tegumental changes in juvenile Fasciola hepatica following treatment in vivo with the experimental fasciolicide, compound alpha

McConville, M.; Brennan, Gerard; Flanagan, Ailish; Edgar, H.W.J.; McCoy, M. A.; Castillo, Rafael; Hernández‐Campos, Alicia; Fairweather, Ian

doi:10.1016/j.vetpar.2008.01.022

Cited by 32 publications

(24 citation statements)

References 24 publications

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“…The general swelling of the basal infolds, mucopolysaccharide masses, mitochondria and cisternae of GER is indicative of disruption of the osmoregulatory function of the tegument (Fairweather et al 1999). Similar observations have been made in previous studies involving TCBZ.SO (Stitt and Fairweather 1994;Halferty et al 2009a) and various other fasciolicides (Fairweather et al 1986;Skuce et al 1987;Skuce and Fairweather 1990;Anderson and Fairweather 1995;Meaney et al 2004Meaney et al , 2005Meaney et al , 2007McConville et al 2006McConville et al , 2007McConville et al , 2008McConville et al , 2009bMcKinstry et al 2007McKinstry et al , 2009Halferty et al 2009b). …”

Section: Discussionsupporting

confidence: 89%

“…Co-incubation of MTZ with TCBZ resulted in an accumulation of secretory bodies just below the apical plasma membrane. This, too, is indicative of a stress response by the fluke and is a common reaction to treatment with other fasciolicidal drugs, as it serves as a survival mechanism to replace damaged tegument (Fairweather et al 1986;Stitt and Fairweather 1994;Buchanan et al 2003;Meaney et al 2004Meaney et al , 2005Meaney et al , 2007McConville et al 2006McConville et al , 2007McConville et al , 2008McConville et al , 2009bMcKinstry et al 2007McKinstry et al , 2009Halferty et al 2009a, b;O'Neill et al 2009;Toner et al 2009Toner et al , 2010. Swelling of the mitochondria and cisternae of GER was exacerbated but, more significantly, the production of secretory bodies in the tegumental cells appeared to be affected, as evidenced by the reduced size of the Golgi complexes and the reduced number of secretory bodies in the cells.…”

Section: Discussionmentioning

confidence: 99%

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Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica

et al. 2010

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A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The flavin monooxygenase system (FMO) was inhibited using methimazole (MTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The FMO system was inhibited by a 2-h pre-incubation in methimazole (100 microM), then incubated for a further 22 h in NCTC medium containing either MTZ; MTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM); MTZ+NADPH+TCBZ (15 microg/ml); or MTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO) (15 microg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than triclabedazole-resistant isolate. However, co-incubation with MTZ+TCBZ, but more particularly MTZ+TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own, with severe swelling of the basal infolds and mucopolysaccharide masses in the syncytium, accompanied by a reduction in numbers of secretory bodies. The synthesis and production of secretory bodies in the tegumental cells was severely affected as well. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes, and this process may play a role in the development of drug resistance.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica

et al. 2010

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“…This is indicative of disruption to the osmoregulatory function of the tegument (Fairweather et al 1999). Similar observations have been made in previous studies involving TCBZ.SO (Stitt and Fairweather 1994;Halferty et al 2009a) and various other fasciolicides (Fairweather et al 1986;Skuce et al 1987;Skuce and Fairweather 1990;Anderson and Fairweather 1995;Meaney et al 2004Meaney et al , 2005Meaney et al , 2007McConville et al 2006McConville et al , 2007McConville et al , 2008McConville et al , 2009McKinstry et al 2007McKinstry et al , 2009Halferty et al 2009b). The severe swelling of the basal infolds would account for the general swelling of the tegument observed in the previous SEM study (Devine et al 2010c); if allowed to continue, this would lead to the sloughing of the tegument.…”

Section: Discussionsupporting

confidence: 89%

Erratum to: Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica

et al. 2011

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A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The cytochrome P450 (CYP 450) enzyme pathway was inhibited using ketoconazole (KTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP 450 system was inhibited by a 2-h pre-incubation in ketoconazole (40 μM), then incubated for a further 22 h in NCTC medium containing either KTZ, KTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM), KTZ+NADPH+ TCBZ (15 μg/ml), or KTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO; 15 μg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with KTZ+ TCBZ, but more particularly KTZ+TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own: for example, there was severe swelling of the basal infolds and their associated mucopolysaccharide masses, accompanied by an accumulation of secretory bodies just below the apex. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis, production, and transport of secretory bodies were badly disrupted. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZresistant flukes and this process may play a role in the development of drug resistance.

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“…The apparent contradiction between drug peaks, drug half-life and drug action has been seen in other drug studies on F. hepatica (e.g. Meaney et al, 2003;McConville et al, 2008McConville et al, , 2009b. For these drugs, which are relatively slow-acting, it may take some time before their action (and the morphological changes they induce) to become apparent; however, the effects are seemingly irreversible, as the drug continues to act following its elimination from the host.…”

Section: Discussionmentioning

confidence: 96%

Adult triclabendazole-resistantFasciola hepatica: morphological changes in the tegument and gut followingin vivotreatment with artemether in the rat model

O'Neill

Johnston²,

Halferty³

et al. 2009

J. Helminthol.

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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 timedependent 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.

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Surface and internal tegumental changes in juvenile Fasciola hepatica following treatment in vivo with the experimental fasciolicide, compound alpha

Cited by 32 publications

References 24 publications

Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica

Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica

Erratum to: Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica

Adult triclabendazole-resistantFasciola hepatica: morphological changes in the tegument and gut followingin vivotreatment with artemether in the rat model

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