Schistosoma mansoni sarco/endoplasmic reticulum Ca 2+ ATPases (SERCA): role in reduced sensitivity to praziquantel
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MINI-REVIEW
Schistosoma mansoni sarco/endoplasmic reticulum Ca2+ ATPases (SERCA): role in reduced sensitivity to praziquantel Iman F. Abou-El-Naga 1 Received: 9 January 2020 / Accepted: 8 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Praziquantel leads to increase Ca2+ influx and disrupts Ca2+ homeostasis in adult Schistosoma. However, calcium influx is only one component in a series of molecular events leading to the drug effect and some downstream constituents of the cascade that is initiated by this interaction differ between worms with different degrees of susceptibility to praziquantel. Extensive use of the drug raises the concern regarding the selection of drug resistant parasites. SERCA participates in maintenance of Ca2+ homeostasis. Upregulation of SERCA has been found in Schistosoma mansoni worms with reduced sensitivity to praziquantel. This could be due to increase cytosolic Ca2+, activation of calmodulin kinase II or may be due to SR/ER stress generated from oxidative stress that leads to impaired protein degradation. The significance of SERCA up-regulation is related to counter action of the drug effect by increasing the worm capacity to restore Ca2+ homeostasis, reducing cytosolic Ca2+ followed by lowering mitochondria Ca2+ and consequently inhibition of apoptosis beside its relation to P-glycoprotein. In schistosomes with reduced sensitivity to praziquantel, the agitations produced by Ca2+ influx and the downstream component of the cascade that is initiated by this interaction may be opposed by up-regulation of SERCA and possibly by certain elements of Ca2+ signaling which modulate the process determining cells entrance in the apoptotic state. Revealing the principal mechanisms of up-regulation of SERCA and its significance in reducing the effect of the drug could lead to possible strategies to reverse drug resistance or develop alternative therapies. Keywords SERCA . Ca2+ ATPases . Schistosoma mansoni . PZQ . Resistance . Calcium
Introduction Schistosomiasis is an important waterborne parasitic disease caused by helminth worms of genus Schistosoma, with three main species (S. mansoni, S. haematobium and S. japonicum) accounting for the majority of human infections. It is considered one of the most prevalent neglected tropical diseases, constituting a major public health problem and leading to chronic and even debilitating disease that impairs development and productivity. The disease is endemic in 78 countries located in Africa, Asia and the Americas and is responsible for 3.3 million disability adjusted life years (Hotez et al. 2014). Inadequate water supply, poor sanitary conditions as well as low socio-
* Iman F. Abou-El-Naga [email protected] 1
Medical Parasitology Department, Faculty of Medicine, Alexandria University, Egypt, 12 Abdel Hamid El Deeb Street, Tharwat, Alexandria, Egypt
economic development are involved in the prevalence of the disease (Rollinson et al. 2013; Abou-El-Naga 2015). Praziquantel (PZQ) is the drug of choice again
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