Fasciola hepatica: Histological changes in the reproductive structures of triclabendazole (TCBZ)-sensitive and TCBZ-resistant flukes after treatment in vivo with TCBZ and the related benzimidazole derivative, Compound Alpha

Hanna, R.E.B.; Edgar, H.W.J.; McConnell, S.; Toner, Emma; McConville, M.; Brennan, Gerard; Devine, C.; Flanagan, Adrienne M.; Halferty, L.; Meaney, M.; Shaw, Laura Kate; Moffett, D.; McCoy, M. A.; Fairweather, Ian

doi:10.1016/j.vetpar.2009.11.014

Cited by 40 publications

(48 citation statements)

References 31 publications

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“…The changes seen in the testis are the direct consequence of drug action, not the side-effect of another action causing deterioration of the fluke. As further corroboration of this, no changes were observed in the testes of the TCBZ-resistant Sligo isolate following treatment in vivo with compound alpha (Hanna et al 2010). Disruption of the testes and other components of the egg production machinery (ovary, vitellaria, Mehlis' gland, and uterus) are likely to have an impact on egg production: fewer eggs may be produced, they may be abnormal, and this may impair their ability to embryonate and hatch properly.…”

Section: Discussionsupporting

confidence: 59%

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Fasciola hepatica: disruption of spermatogenesis by the fasciolicide compound alpha

et al. 2009

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Sheep infected with the triclabendazole-susceptible Cullompton isolate of Fasciola hepatica were dosed with 15 mg/kg of compound alpha at 12 weeks post-infection. Adult flukes were recovered from the bile ducts at 24, 48, and 72 h post-treatment (p.t.). Changes to the spermatogenic cells in the testis were examined by histology and transmission electron microscopy. Disruption to the testes became increasingly severe over time. The testis tubules shrank in size, became vacuolated, and contained fewer cells. Identification of cell types became difficult, and apoptotic eosinophilic bodies were the predominant feature at 72 h p.t. Changes to the spermatogonia were evident at 24 h p.t., the cells containing swollen and electron-lucent mitochondria. The proportion of tertiary spermatogonia increased at 48 h p.t., and they showed signs of autophagy. Multinucleate spermatogonia were a feature of drug treatment at this time point, and they contained autophagic vacuoles. By 72 h p.t., it was difficult to identify primary and secondary spermatogonia, and there were no recognisable clusters of tertiary spermatogonia. Most spermatogonial cells were multinucleate and in the process of breaking down. With regard to the primary spermatocytes, fragmentation of the cytophore was observed at 24 h p.t. Intact rosettes were rare after 48 h treatment; collections of cells were seen, but were not organised into clusters. By 72 h p.t., no spermatocyte cells could be recognised. The results indicate that spermatogenesis was severely affected by compound alpha.

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Section: Discussionsupporting

confidence: 59%

“…A separate paper details disruption to the ovary, vitelline follicles, and Mehlis' gland and lack of eggs in the uterus at 48 h p.t. (Hanna et al 2010). Abnormal egg production is evident earlier (at 24 h p.t.…”

Section: Discussionmentioning

confidence: 99%

Fasciola hepatica: disruption of spermatogenesis by the fasciolicide compound alpha

et al. 2009

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“…Compound alpha was more disruptive than TCBZ in relation to the impact on the sustentacular cell network and on the cytophore of the primary spermatocyte cell rosettes. It seems likely that the failure of mitosis and meiosis in the testis of flukes treated with these two benzimidazoles triggers apoptosis and that a combination of the two phenomena leads to a decrease in the cell population in the tubules, as suggested by Hanna et al (2010).…”

Section: Discussionmentioning

confidence: 99%

“…Much of the body of the fluke is dedicated to the production of the gametes, in an effort to maximise fecundity and ensure continuation of the life cycle. The consequent high rate of metabolic activity and cell division that occurs in the testis makes this tissue useful for studying anthelminticinduced effects (eg Dawes 1966aDawes , b, 1967Dawes , 1968Stammers 1975aStammers , b, 1976Hanna et al 2010;McConville et al 2010). This is of particular significance as triclabendazole (TCBZ), like other benzimidazole drugs, is believed to target the microtubule component of the cytoskeleton, thus blocking mitotic and meiotic cell division and the differentiation of spermatogenic and spermiogenic cells (Stitt and Fairweather 1992).…”

Section: Introductionmentioning

confidence: 99%

Fasciola hepatica: time-dependent disruption of spermatogenesis following in vivo treatment with triclabendazole

et al. 2011

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Sheep infected with the Cullompton isolate of Fasciola hepatica were treated with triclabendazole at a concentration of 10 mg/kg at 12 weeks post-infection. Adult flukes were recovered from the liver and, where present, from the gall bladder at 48, 72 and 96 h post-treatment (pt). Gross changes to the spermatogenic cells of the testis were examined by histology and ultrastructural alterations were visualised via transmission electron microscopy. Disruption was progressive in nature, with the testis tubules becoming shrunken, vacuolated and gradually more denuded of cellular content over the 96-h time period. From 48 h pt, the number of primary and secondary spermatogonia decreased and multinucleate spermatogonial cells were frequent. Later, developmental stages were uncommon, giving rise to much empty space within the tubules. By 72 h pt, the tubules contained many apoptotic and degraded cells and had an extremely disorganised appearance. At 96 h pt, the tubules were almost completely empty, with the exception of the remains of degraded spermatogenic cells. These results indicate that triclabendazole severely disrupts spermatogenesis in the liver fluke from 48 h pt in vivo.

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“…The Cullompton isolate originated from a field isolate in Cullompton, Devon, England. This isolate has been shown to be susceptible to TCBZ action in vivo and to its sulphoxide metabolite in vitro (Robinson et al 2002;McCoy et al 2005;McConville et al 2006McConville et al , 2009aMeaney et al 2006Meaney et al , 2007Halferty et al 2008Halferty et al , 2009Hanna et al 2010;Devine et al 2009Devine et al , 2010aToner et al 2009Toner et al , 2010. Adult flukes (at least 12 weeks old) were removed from the bile ducts of rats under sterile conditions in a laminar flow cabinet and washed repeatedly in warm (37°C) NCTC 135 culture medium (pH 7.4) containing antibiotics (penicillin 50 IU/ml; streptomycin 50 μg/ ml).…”

Section: Methodsmentioning

confidence: 99%

Enhancement of the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica using the metabolic inhibitor ketoconazole

et al. 2010

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A study has been carried out to investigate whether the action of triclabendazole (TCBZ) is altered by using the metabolic inhibitor, ketoconazole (KTZ) to inhibit the cytochrome P450 (CYP 450) system within Fasciola hepatica. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP 450 enzyme system was inhibited by a 2 h pre-incubation in KTZ (40 microM). Flukes were 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 microg/ml); or KTZ + NADPH + triclabendazole sulphoxide (TCBZ.SO;15 microg/ml). Morphological changes resulting from drug treatment and following metabolic inhibition were assessed using scanning electron microscopy. After treatment with either TCBZ or TCBZ.SO alone, there was greater disruption to the TCBZ-susceptible isolate than the TCBZ-resistant isolate. However, co-incubation with KTZ and TCBZ/TCBZ.SO led to more severe surface changes to the TCBZ-resistant isolate than with each drug on its own, with greater swelling and blebbing of the tegument and even the loss of the apical plasma membrane in places. With the Cullompton isolate, there was limited potentiation of drug action in combination with KTZ, and only with TCBZ.SO. The results support the concept of altered drug metabolism within TCBZ-resistant isolates and indicate that this process may play a role in the development of drug resistance.

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Fasciola hepatica: Histological changes in the reproductive structures of triclabendazole (TCBZ)-sensitive and TCBZ-resistant flukes after treatment in vivo with TCBZ and the related benzimidazole derivative, Compound Alpha

Cited by 40 publications

References 31 publications

Fasciola hepatica: disruption of spermatogenesis by the fasciolicide compound alpha

Fasciola hepatica: disruption of spermatogenesis by the fasciolicide compound alpha

Fasciola hepatica: time-dependent disruption of spermatogenesis following in vivo treatment with triclabendazole

Enhancement of the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica using the metabolic inhibitor ketoconazole

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