Drug Targets And Mechanisms Of The Praziquantel (PZQ) Activity On Schistosoma Japonicum

BackgroundPraziquantel (PZQ) has been introduced for the treatment of schistosomiasis over 30 years, but its mechanism of action remains unknown. Recent evidence points to voltage-gated calcium channels (VGCCs) in schistosomes as possible drug targets, based on structural and functional characteristics of theβ-subunits of these channels, and the death of schistosomes may be due to the disruption of Ca2+ homeostasis in adult schistosomes by PZQ ultimately.ObjectiveIn order to offer us more evidences for identifying the mode of action of PZQ, S. jiaponicum were subjected in vitro to pharmacological agents capable of disturbing the functioning of calcium channels, and three different conditions leading to the disruption of calcium channel function were investigated.Methods1. To observe the effects of calcium channel blockers (CCBs) on the survival and the ultrastructural changes of S. japonicum treated with praziquantel in vitro2. To observe the effects of actin depolymerizing/stabilizing agents on the survival and the ultrastructure of S. japonicum treated with praziquantel in vitro3. To observe the effects of protein kinase C (PKC) inhibitors or activation agents on the survival of S. japonicum treated with praziquantel in vitro4. Studies in vivo and in vitro on the effects of hypericin on S. japonicumResults1.Some of L-type calcium channel blockers, such as nitrendipine and nifedipine, were able to partially inhibited the ability of PZQ to kill S. japonicum adult male worms, and the ultrastructure of the worm body wall with minor injuries.2.The killing activity of PZQ to S. japonicum was completely blocked by CyD, and the ultrastructure of the worm body wall with no damages.3.The PKC inhibitor hypericin had a significant ability to kill S. japonicum in vitro, and it could also kill schistosomes in vivo.ConclusionThis study is consistent with the hypothesis that schistosome VGCCs are involved in the mechanism of action of PZQ.1.The binding sites of L-type calcium channel blockers (nitrendipine and nifedipine) in VGCCs of S. japonicum maybe involved in the mechanism of PZQ activity.2.The disruption of the actin cytoskeleton induced by CyD probly blocks the signal transduction of schistosomes after PZQ stimulation, and the signal transduction pathway perhaps involving many other factors instead of only Ca2+.3.The ultrastructural damages of the body wall of schistosomes may be associated with the secondary effects of spastic paralysis of schistosomes produced by PZQ instead of a direct effect of PZQ activity.4.Hypericin has potential anti-schistosome action.