Hostname: page-component-8448b6f56d-cfpbc Total loading time: 0 Render date: 2024-04-17T19:48:55.768Z Has data issue: false hasContentIssue false
  • English
  • Français

The anti-schistosomal drug praziquantel is an adenosine antagonist

Published online by Cambridge University Press:  12 April 2007

F. ANGELUCCI ,
A. BASSO ,
A. BELLELLI ,
M. BRUNORI ,
L. PICA MATTOCCIA  and
C. VALLE
F. ANGELUCCI
Affiliation:
Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Istituto Pasteur – Fondazione Cenci Bolognetti, Università di Roma “Sapienza”, Piazzale Aldo Moro 5, 00185 Roma, Italy
A. BASSO
Affiliation:
Istituto di Biologia Cellulare del CNR, Via Ramarini 32, Monterotondo, 00016 Roma, Italy
A. BELLELLI*
Affiliation:
Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Istituto Pasteur – Fondazione Cenci Bolognetti, Università di Roma “Sapienza”, Piazzale Aldo Moro 5, 00185 Roma, Italy
M. BRUNORI
Affiliation:
Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Istituto Pasteur – Fondazione Cenci Bolognetti, Università di Roma “Sapienza”, Piazzale Aldo Moro 5, 00185 Roma, Italy
L. PICA MATTOCCIA
Affiliation:
Istituto di Biologia Cellulare del CNR, Via Ramarini 32, Monterotondo, 00016 Roma, Italy
C. VALLE
Affiliation:
Istituto di Biologia Cellulare del CNR, Via Ramarini 32, Monterotondo, 00016 Roma, Italy
*
*Corresponding author: Department of Biochemical Sciences “A. Rossi Fanelli”, University of Rome “Sapienza”, P.le Aldo Moro 5, 00185 Rome, Italy. Tel: +39 06 49910236. Fax: +39 06 4440062. E-mail: andrea.bellelli@uniroma1.it
Get access Rights & Permissions [Opens in a new window]

Summary

The mechanism of action of praziquantel (PZQ), the drug of choice against schistosomiasis, is still unclear. Since exposure of schistosomes to the drug is associated with calcium influx and muscular contraction, calcium channels have been suggested as the target, although direct combination of PZQ with their subunits was never demonstrated. We report a hitherto unknown effect of PZQ, namely the inhibition of nucleoside uptake, as observed in living worms using radio-isotope labelled adenosine and uridine. This effect is clearly seen in schistosomes but is absent in mammalian cells in culture. Moreover it is a specific pharmacological effect seen exclusively with the active levo-R(−)stereo isomer of the drug, and is shared by at least one benzodiazepine having antischistosomal activity. This novel effect acquires significance given that schistosomes cannot synthesize purine nucleosides de novo. A possible relationship between this novel effect and the known action of PZQ on calcium channels is discussed, since adenosine is known to bind to specific receptors and to behave as an indirect antagonist of calcium release in mammalian cells. If calcium channels were correlated with adenosine receptors also in schistosomes, as they are in mammals, this would support the hypothesis that PZQ-induced calcium influx may be correlated to adenosine receptor blockade.

Keywords

praziquantelschistosomiasisnucleoside uptakeadenosine
Type
Research Article
Information
Parasitology , Volume 134 , Issue 9 , August 2007 , pp. 1215 - 1221
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Bennett, J. L. (1980). Characteristics of antischistosomal benzodiazepine binding sites in Schistosoma mansoni. Journal of Parasitology 66, 742–747.CrossRefGoogle ScholarPubMed
Cioli, D., Pica-Mattoccia, L. and Archer, S. (1995). Antischistosomal drugs: past, present … and future? Pharmacology and Therapeutics 68, 35–85.CrossRefGoogle ScholarPubMed
Cioli, D. and Pica Mattoccia, L. (2003). Praziquantel. Parasitology Research 90, S3–S9.CrossRefGoogle ScholarPubMed
Chitsulo, L., Loverde, P. and Engels, D. (2004). Schistosomiasis. Nature Reviews Microbiology 2, 12–13.CrossRefGoogle ScholarPubMed
Gardner, D. R. and Brezden, B. L. (1984). The sites of action of praziquantel in a smooth muscle of Lymnaea stagnalis. Canadian Journal of Physiology and Pharmacology 62, 282–287.CrossRefGoogle Scholar
Greenberg, R. M. (2005). Are Ca2+ channels targets of praziquantel action? International Journal for Parasitology 35, 1–9.CrossRefGoogle ScholarPubMed
Frischknecht, R. and Ferrero, J. D. (1985). Adenosine increases an internal calcium store in the smooth muscle of guinea-pig Taenia coli. European Journal of Pharmacology 110, 109–112.CrossRefGoogle ScholarPubMed
Gonnert, R. and Andrews, P. (1977). Praziquantel, a new broad-spectrum antischistosomal agent. Zeitschrift für Parasitenkunde 52, 129–150.CrossRefGoogle Scholar
Hu, P. S., Lindgren, E., Jacobson, K. A. and Fredholm, B. B. (1987). Interaction of dihydropyridine calcium channel agonists and antagonists with adenosine receptors. Pharmacology and Toxicology 61, 121–125.CrossRefGoogle ScholarPubMed
Jacobson, K. A. and Gao, Z. (2006). Adenosine receptors as therapeutic targets. Nature Reviews Drug Discovery 5, 247–264.CrossRefGoogle ScholarPubMed
Jaffe, J. J., Meymarian, E. and Doremus, H. M. (1971). Antischistosomal action of tubercidin administered after absorption into red cells. Nature, London 230, 408–409.CrossRefGoogle ScholarPubMed
Jeziorski, M. C. and Greenberg, R. M. (2006). Voltage-gated calcium channel subunits from platyhelminths: potential role in praziquantel action. International Journal for Parasitology 36, 625–632.CrossRefGoogle ScholarPubMed
Kohn, A. B., Roberts-Misterly, J. M., Anderson, P. A., Khan, N. and Greenberg, R. M. (2003). Specific sites in the Beta Interaction Domain of a schistosome Ca2+ channel beta subunit are key to its role in sensitivity to the anti-schistosomal drug praziquantel. Parasitology 127, 349–356.CrossRefGoogle Scholar
Levy, M. G. and Read, P. C. (1975). Purine and pyrimidine transport in Schistosoma mansoni. Journal of Parasitology 61, 627–632.CrossRefGoogle ScholarPubMed
Listos, J., Malec, D. and Fidecka, S. (2005). Influence of adenosine receptor agonists on benzodiazepine withdrawal signs in mice. European Journal of Pharmacology 523, 71–78.CrossRefGoogle ScholarPubMed
Oliveira, L., Timoteo, M. A. and Correia-de-Sa, P. (2004). Tetanic depression is overcome by tonic adenosine A(2A) receptor facilitation of L-type Ca(2+) influx into rat motor nerve terminals. Journal of Physiology 560, 157–168.CrossRefGoogle ScholarPubMed
Pica-Mattoccia, L. and Cioli, D. (2004). Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment. International Journal for Parasitology 34, 527–533.CrossRefGoogle ScholarPubMed
Pica-Mattoccia, L., Valle, C., Basso, A., Troiani, A. R., Vigorosi, F., Liberti, P., Festucci, A. and Cioli, D. (2007). Cytochalasin D abolishes the schistosomicidal activity of praziquantel. Experimenal Parasitology 115, 344–351.CrossRefGoogle ScholarPubMed
Ralevic, V. and Burnstock, G. (1998). Receptors for purines and pyrimidines. Pharmacological Reviews 50, 415–479.Google ScholarPubMed
Redman, C. A., Robertson, A., Fallon, P. G., Modha, J., Kusel, J. R., Doenhoff, M. J. and Martin, R. J. (1996). Praziquantel: an urgent and exciting challenge. Parasitology Today 12, 14–20.CrossRefGoogle ScholarPubMed
Rowlett, J. K., Rowlett, J. K., Platt, D. M., Lelas, S., Atack, J. R. and Dawson, G. R. (2005). Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates. Proceedings of the National Academy of Sciences, USA 102, 915–920.CrossRefGoogle ScholarPubMed
Schaufele, P., Schumacher, P., Acevedo, C. G. and Contreras, E. (1995). Diazepam, adenosine analogues and calcium channel antagonists inhibit the contractile activity of the mouse urinary bladder. Archives of International Pharmacodynamics and Therapeutics 329, 454–466.Google ScholarPubMed
Seubert, C. N., Morey, T. E., Martynyuk, A. E., Cucchiara, R. F. and Dennis, M. D. (2000). Midazolam selectively potentiates the A2A-adenosine but not A1-receptor-mediated effects of adenosine. Anesthesiology 92, 567–577.CrossRefGoogle Scholar
Stone, T. W. (1999). Actions of benzodiazepines and the benzodiazepine antagonist flumazenil may involve adenosine. Journal of Neurological Sciences 163, 199–200.Google ScholarPubMed
Suchail, S., Sarciron, M. E. and Petavy, A. F. (1998). Purine metabolism in Echinococcus multilocularis. Comparative Biochemistry and Physiology, B 120, 633–637.CrossRefGoogle ScholarPubMed
Swanson, T. H. and Green, C. L. (1986). Nifedipine: more than a calcium channel blocker. General Pharmacology 17, 255–260.CrossRefGoogle ScholarPubMed
Van Rhee, A. M., Jiang, J. L., Melman, N., Olah, M. E., Stiles, G. L. and Jacobson, K. A. (1996). Interaction of 1,4-dihydropyridine and pyridine derivatives with adenosine receptors: selectivity for A3 receptors. Journal of Medicinal Chemistry 39, 2980–2989.CrossRefGoogle ScholarPubMed
Wong, P. C. and Ko, R. C. (1979). De novo purine ribonucleotide biosynthesis in adult Angiostrongylus cantonensis (Nematoda: Metastrongyloidea). Comparative Biochemistry and Physiology, B 62, 129–132.CrossRefGoogle ScholarPubMed
Wong, P. C. and Yeung, S. B. (1981). Pathways of purine ribonucleotide biosynthesis in the adult worm Metastrongylus apri (Nematoda: Metastrongyloidea) from pig lung. Molecular and Biochemical Parasitology 2, 285–293.CrossRefGoogle ScholarPubMed
Zapata, R., Navarro, A., Canela, E. I., Franco, R., Lluis, C. and Mallol, J. (1997). Regulation of L-type calcium channels in GH4 cells via A1 adenosine receptors. Journal of Neurochemistry 69, 2546–2554.CrossRefGoogle ScholarPubMed