| Summary: | Using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and histology, the effects of artemisinin compounds on the tegumental surface and ultrastructure of the liver fluke, Fasciola hepatica, were assessed. The histology and SEM findings revealed that treatment of flukes with the artemisinin-type compounds, artemether, artesunate and OZ78, resulted in relatively little disruption to the external tegumental surface when compared with other fasciolicides. In contrast, changes to the ultrastructure, as examined by TEM, were rapid, severe and progressive, particularly in the gut and reproductive tissues. That changes in the gut occurred rapidly following administration, and were more extensive than those observed in the tegument, suggests that an oral route of uptake may predominate for these compounds. Experiments were undertaken using three different fluke isolates, two of which have been previously confirmed as being resistant to the current drug of choice, triclabendazole (TCBZ). The nature and extent of the changes in fluke tissues appeared to be similar across the isolates, confirming that artemisinin-type compounds have equal activity against both TCBZ-susceptible and TCBZ-resistant fluke. With each of the three compounds, the changes observed in fluke tissues were distinct from those induced by other known fasciolicides, being typified by widespread disruption to the mitochondria and the cisternae of the ger, particularly in the gut. As time progressed post-treatment, inhibition of spermatogenesis and oogenesis became evident, with widespread apoptosis observed in both tissues. The observed changes, particularly to the cisternae of the ger, link well to the suggested mechanism of action for these compounds, via inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), but suggest that a less-specific dual mechanism of action may be more likely. Finally, the current study established a time-scale for the action of artemisinin-type compounds against fluke, and substantiated previous concerns over the potential toxicity of artesunate when administered at high doses.
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