Abstract
After almost 50 years of praziquantel (PZQ) research, Park and Marchant (Trends Parasitol 36:182–194, 2020) described the Ca++-permeable transient receptor potential (TRP) channel Sm.TRPMPZQ in Schistosoma mansoni as target of PZQ. Here we describe the deadly cascade in schistosomes which is induced by the (R)-PZQ enantiomer that includes contemporaneous stereoselective activation of Sm.TRPMPZQ-mediated Ca++ influx, disturbed Ca++ homeostasis, Ca++-dependent spastic paralysis, and Ca++- and PZQ-dependent disruption of parasitic teguments. Under normal conditions, there is a reversible balance between bilayer, isotropic, and HII phases in biological membranes (Jouhet 2013). In vitro, we could observe an irreversible but not stereoselective transition to the HII phase in liposomes consisting of phosphatidylethanolamine (PE) and phosphatidylserine (PS), two naturally occurring phospholipids in schistosomes, by the concerted action of Ca++ and PZQ (Harder 2013). HII structures are a prerequisite for induction of fusion processes (Jouhet 2013), which, indeed, become visible as blebs, vacuolation processes, and large balloon-like surface exudates in a large variety of PZQ-sensitive parasitic flukes and cestodes after PZQ treatment. These tegument damages are irreversible. As homologs of Sm.TRPMPZQ are also present in the other trematodes S. japonicum, S. haematobium, or Clonorchis sinensis and cestodes Taenia solium, Echinococcus multilocularis, or Hymenolepis microstoma (Park and Marchant, Trends Parasitol 36:182–194, 2020), it is suggested that a similar deadly cascade will be operating generally in PZQ-sensitive parasites.
Highlights
Praziquantel (PZQ), the drug of choice against a variety of blood, liver, lung, intestinal flukes, and cestodes in human and veterinary medicine, had been discovered by a joint cooperation between Bayer AG and E
The anthelmintic activities against trematodes and cestodes of PZQ have been reviewed in a large variety of publications over a long period of time
Tegument damage by PZQ is only induced in presence of Ca++, whereas PZQ-evoked vacuolation does not occur in Ca++-free media or in Ca++depleted schistosomes or in the presence of an excess of Mg++ (Xiao et al 1984; Andrews 1985; Park and Marchant 2020)
Summary
Praziquantel (PZQ), the drug of choice against a variety of blood, liver, lung, intestinal flukes, and cestodes in human and veterinary medicine, had been discovered by a joint cooperation between Bayer AG and E. The observed stereoselectivity of tegument damage by (R)-PZQ may be due more to the stereoselective binding of drug to Sm.TRPMPZQ, present in schistosomes (Park and Marchant 2020).
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