Fasciola hepatica: ultrastructural effects of a combination of triclabendazole and clorsulon against mature fluke

Meaney, M.; Allister, J.; McKinstry, B.; McLaughlin, Kylie A.; Brennan, Gerard; Forbes, Andrew Benjamin; Fairweather, Ian

doi:10.1007/s00436-006-0378-6

Cited by 32 publications

(32 citation statements)

References 29 publications

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“…It is not always possible to link particular morphological changes to uncoupling activity, but such disruption would be compatible with the changes to the mitochondria and ger cisternae, the decreased secretory activity in the gastrodermal cells and the increased number of autophagic vacuoles. Similar changes have been observed following treatment with closantel, another flukicide that targets oxidative phosphorylation in the fluke (Verheyen et al 1980;Skuce and Fairweather 1990), and with clorsulon, which disrupts glycolysis (Meaney et al 2004(Meaney et al , 2005b(Meaney et al , 2007.…”

Section: Discussionsupporting

confidence: 50%

“…These changes could be the cause of the gross swelling of the fluke observed previously (McKinstry et al 2003). Swelling of the basal infolds, which leads to the detachment of the syncytium, has been observed following treatment with closantel and clorsulon, two other fasciolicides that affect energy metabolism, as described above (Skuce and Fairweather 1990;Meaney et al 2004Meaney et al , 2005bMeaney et al , 2007. Having said that, swelling of the basal infolds also occurs after treatment with drugs that are not believed to target energy metabolism, such as triclabendazole and compound alpha (Stitt and Fairweather 1994;McConville et al 2006McConville et al , 2007.…”

Section: Discussionmentioning

confidence: 96%

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Ultrastructural changes induced in the tegument and gut of Fasciola hepatica following in vivo and in vitro drug treatment with nitroxynil (Trodax)

McKinstry¹,

Brennan²,

Halferty³

et al. 2007

Parasitol Res

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Male Sprague-Dawley rats were dosed orally with nitroxynil at a concentration of 40 mg/kg, and adult Fasciola hepatica were recovered after 24, 48 and 72 h. Fine structural changes to the tegument and gut were monitored by transmission electron microscopy. Flukes were also incubated for 24 h in vitro in nitroxynil at a concentration of 100 microg/ml. Following treatment in vivo, there was an accumulation and accelerated release of secretory bodies at the apex of the tegumental syncytium. Some swelling of the mucopolysaccharide masses surrounding the basal infolds was evident after 48 and 72 h. There was an initial accumulation of T1 secretory bodies at the base of the syncytium, but this decreased at 72 h, coinciding with a decline in their production in the tegumental cells. The mitochondria were consistently swollen in the tegumental cells. At 72 h, large vacuolations were observed between the muscle layers and there was flooding around the underlying tissues. Some tegumental cells were seen to be degenerating and beginning to disintegrate. After 24 h treatment in vitro, the basal infolds were swollen and the crystalline structure of the spines was disrupted. Flooding of the internal tissues was evident and, in the tegumental cells, Golgi complexes and secretory bodies were absent. The mitochondria in the tegumental cells were swollen. In the gastrodermal cells, changes were evident at the earliest time period in vivo. The lamellae were disrupted, few secretory bodies were present, the mitochondria and cisternae of granular endoplasmic reticulum (ger) were swollen and there was an increased number of secretory bodies. These changes became progressively more severe with time. Similar changes were evident following treatment in vitro; vesiculation of the ger was also seen. The results indicate that oral uptake is the predominant route of entry of nitroxynil into the fluke.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 96%

Ultrastructural changes induced in the tegument and gut of Fasciola hepatica following in vivo and in vitro drug treatment with nitroxynil (Trodax)

McKinstry¹,

Brennan²,

Halferty³

et al. 2007

Parasitol Res

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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: 75%

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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“…This may be due to inhibition of the energy-dependent ion pumps on the tegumental membranes and is evidenced by the swollen mitochondria and cisternae of ger and the presence of lipid droplets, together with the swelling of the basal infolds. Similar changes have been seen following treatment with fasciolicides that are believed to target energy metabolism, including clorsulon, closantel and nitroxynil (Skuce and Fairweather, 1990 ;Meaney et al 2004Meaney et al , 2005Meaney et al , 2007McKinstry et al 2007McKinstry et al , 2009. Alternatively, the flooding may stem from damage to the surface membrane as a result of impairment of production of secretory bodies in the tegumental cells.…”

Section: Discussionmentioning

confidence: 77%

“…Female Wistar rats (purchased from RCC, Itingen, Switzerland) were experimentally infected with metacercarial cysts of the Cullompton isolate, shown in previous experiments to be susceptible to TCBZ in vivo and to its sulphoxide metabolite in vitro (Robinson et al 2002 ;McCoy et al 2005 ;Halferty et al 2008Halferty et al , 2009McConville et al 2006McConville et al , 2009Meaney et al 2006Meaney et al , 2007Devine et al 2009 ;Toner et al 2009). All animals were housed in environmentally-controlled conditions in groups of 4 and afforded 1 week to acclimatize.…”

Section: A T E R I a L S A N D M E T H O D Smentioning

confidence: 99%

Electron microscopical study to assess thein vitroeffects of the synthetic trioxolane OZ78 against the liver fluke,Fasciola hepatica

et al. 2009

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Adult Fasciola hepatica were incubated for 48 h in vitro in the synthetic peroxide, OZ78 at a concentration of 100 mg/ml and then prepared for scanning and transmission electron microscopy. There was limited disruption to the external fluke surface, with only slight swelling and blebbing of the interspinal tegument in the midbody and ventral tail regions. By contrast, significant disruption was observed to the ultrastructure of the tegument and subtegumental tissues. There was severe swelling of the basal infolds in the tegumental syncytium and the flooding spread internally to affect the subtegumental tissues. In the tegumental system, there was swelling of the cisternae of granular endoplasmic reticulum and of the mitochondria, with the latter showing signs of breaking down. Autophagic vacuoles and lipid droplets were present and the synthesis of tegumental secretory bodies was much reduced. The gastrodermal cells were severely affected, with swelling and degeneration of the mitochondria and the presence of autophagic vacuoles and lipid droplets. The granular endoplasmic reticulum was swollen and vesiculated and the cells contained few secretory bodies. Both the vitelline and testis follicles showed evidence of extensive cellular disruption and degeneration. This study confirms previous data indicating the potential flukicidal activity of OZ78.

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Fasciola hepatica: ultrastructural effects of a combination of triclabendazole and clorsulon against mature fluke

Cited by 32 publications

References 29 publications

Ultrastructural changes induced in the tegument and gut of Fasciola hepatica following in vivo and in vitro drug treatment with nitroxynil (Trodax)

Ultrastructural changes induced in the tegument and gut of Fasciola hepatica following in vivo and in vitro drug treatment with nitroxynil (Trodax)

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

Electron microscopical study to assess thein vitroeffects of the synthetic trioxolane OZ78 against the liver fluke,Fasciola hepatica

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