Towards an understanding of the mechanism of action of praziquantel

Abstract

Although praziquantel (PZQ) has been used to treat schistosomiasis for over 20 years its mechanism of action remains unknown. We have developed an assay based on the transcriptional response of Schistosoma mansoni PR-1 to heat shock to confirm that while 6-week post-infection (p.i.) schistosomes are sensitive to PZQ, 4-week p.i. schistosomes are not. Further, we have used this assay to demonstrate that in mice this sensitivity develops between days 37 and 40 p.i. When PZQ is linked to the fluorophore BODIPY to aid microscopic visualization, it appears to enter the cells of intact 4 and 6-week p.i. schistosomes as well as mammalian NIH 3T3 cells with ease suggesting that the differential effects of PZQ is not based on cell exclusion. A transcriptomal analysis of gene expression between 4 and 6 weeks p.i. revealed 607 up-regulated candidate genes whose products are potential PZQ targets. A comparison of this gene list with that of genes expressed by PZQ sensitive miracidia reduced this target list to 247 genes, including a number involved in aerobic metabolism and cytosolic calcium regulation. Finally, we also report the effect of an in vitro sub-lethal exposure of PZQ on the transcriptome of S. mansoni PR-1. Annotation of genes differentially regulated by PZQ exposure suggests that schistosomes may undergo a transcriptomic response similar to that observed during oxidative stress.

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

“…These studies revealing genes that might be evolved in aerobic metabolism and cytosolic calcium regulation, suggesting that schistosomes undergo a transcriptomic response similar to that seen during oxidative stress (74). Moreover, it was demonstrated that CamKII (calcium/calmodulin-dependent protein kinase type II) appears to play a key role in the mode of action of PZQ1 and hence might be considered a promising novel drug target (76,77).…”

“…High-throughput transcriptomic approaches have been employed to address the refractory/susceptible nature of the developmental stages of schistosomes in terms of PZQ1 activity (73)(74)(75)(76)(77). These studies revealing genes that might be evolved in aerobic metabolism and cytosolic calcium regulation, suggesting that schistosomes undergo a transcriptomic response similar to that seen during oxidative stress (74).…”

Schistosomiasis in the People's Republic of China: the Era of the Three Gorges Dam

“…on May 9, 2018 by guest http://cmr.asm.org/ and its precise mechanism of action remains unknown (9). A recent study implicated myosin light chain as an alternative target of PZQ (71).…”

Regulatory Influence of Procambarusclarkii, Girad (Decapoda: Cambaridae) On Schistosome-Transmitting Snails in Lotic Habitats within the River Athi Basin, Kenya

“…Today, public health campaigns in endemic regions focus on mass drug administration using the oral drug, praziquantel (PZQ) [3]. Although PZQ is fairly efficacious against the sexually mature forms of the parasite, it is often unable to kill juvenile schistosomes present in the human body [4]. Additionally, there is concern that with the intensive use of PZQ drug resistance could render PZQ ineffective; given that drug resistant strains can easily be selected in the laboratory [5] and field derived strains with reduced susceptibility have been described [6].…”