Effects of dipyridamole on Plasmodium falciparum -infected erythrocytes

Akaki, Mayumi; Nakano, Yamaji; Ito, Yoshihiro; Nagayasu, Eiji; Aikawa, Masamichi

doi:10.1007/s00436-002-0690-8

Cited by 11 publications

(9 citation statements)

References 19 publications

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“…A 50 % inhibition of P. falciparum has been observed at 30 nM dipyridamole after 24 h treatment [43]. However, the reported antimalarial activity of dipyridamole [42] is strong compared with that of zaprinast observed here. Dipyridamole is known to have various effects such as nucleoside transport inhibition [44], anti-tumour-drug-effluxing inhibition [45], blockage of chloride transport [46], band-3-mediated anion-exchange inhibition [47] and antioxidant properties [48].…”

Section: Discussioncontrasting

confidence: 46%

“…In addition to zaprinast (IC 50 = 3.8 µM), PfPDE1 was also inhibited moderately by dipyridamole (IC 50 = 22 µM). The antimalarial activity of dipyridamole has been reported previously [42,43]. A 50 % inhibition of P. falciparum has been observed at 30 nM dipyridamole after 24 h treatment [43].…”

Section: Discussionmentioning

confidence: 72%

“…Dipyridamole is known to have various effects such as nucleoside transport inhibition [44], anti-tumour-drug-effluxing inhibition [45], blockage of chloride transport [46], band-3-mediated anion-exchange inhibition [47] and antioxidant properties [48]. It has been assumed that the antimalarial effects of dipyridamole are associated with the inhibition of some transport system [42]. On the other hand, dipyridamole is also established as a potent PDE inhibitor [49]; nevertheless, the involvement of its inhibitory effects on PDEs in the organism was not discussed in [42].…”

Section: Discussionmentioning

confidence: 99%

“…It has been assumed that the antimalarial effects of dipyridamole are associated with the inhibition of some transport system [42]. On the other hand, dipyridamole is also established as a potent PDE inhibitor [49]; nevertheless, the involvement of its inhibitory effects on PDEs in the organism was not discussed in [42]. Dipyridamole-sensitive PDE may be included in the three other Plasmodium PDEs and dipyridamole might exhibit more potent antimalarial effects through inhibition of the enzyme than zaprinast.…”

Section: Discussionmentioning

confidence: 99%

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PfPDE1, a novel cGMP-specific phosphodiesterase from the human malaria parasitePlasmodium falciparum

Yuasa

Mi-ichi

Tamaki

et al. 2005

Biochemical Journal

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This is the first report of molecular characterization of a novel cyclic nucleotide PDE (phosphodiesterase), isolated from the human malaria parasite Plasmodium falciparum and designated PfPDE1. PfPDE1 cDNA encodes an 884-amino-acid protein, including six putative transmembrane domains in the N-terminus followed by a catalytic domain. The PfPDE1 gene is a single-copy gene consisting of two exons and a 170 bp intron. PfPDE1 transcripts were abundant in the ring form of the asexual blood stages of the parasite. The C-terminal catalytic domain of PfPDE1, produced in Escherichia coli, specifically hydrolysed cGMP with a K(m) value of 0.65 microM. Among the PDE inhibitors tested, a PDE5 inhibitor, zaprinast, was the most effective, having an IC50 value of 3.8 microM. The non-specific PDE inhibitors IBMX (3-isobutyl-1-methylxanthine), theophylline and the antimalarial chloroquine had IC50 values of over 100 microM. Membrane fractions prepared from P. falciparum at mixed asexual blood stages showed potent cGMP hydrolytic activity compared with cytosolic fractions. This hydrolytic activity was sensitive to zaprinast with an IC50 value of 4.1 microM, but insensitive to IBMX and theophylline. Furthermore, an in vitro antimalarial activity assay demonstrated that zaprinast inhibited the growth of the asexual blood parasites, with an ED50 value of 35 microM. The impact of cyclic nucleotide signalling on the cellular development of this parasite has previously been discussed. Thus this enzyme is suggested to be a novel potential target for the treatment of the disease malaria.

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Section: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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PfPDE1, a novel cGMP-specific phosphodiesterase from the human malaria parasitePlasmodium falciparum

Yuasa

Mi-ichi

Tamaki

et al. 2005

Biochemical Journal

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“…Dipyridamole inhibits growth of chloroquine-resistant P. falciparum parasites in vitro , though the reported efficacy varies with IC 50 values ranging from 30 nM [31] to 13.9 μM [32]. Dipyridamole inhibits recombinant P. falciparum phosphodiesterase-1, however, the mechanism of dipyridamole’s antiparasitic activity in vitro is not known [33].…”

Section: Discussionmentioning

confidence: 99%

Malaria parasite type 4 equilibrative nucleoside transporters (ENT4) are purine transporters with distinct substrate specificity

Frame

Merino

Schramm

et al. 2012

Biochemical Journal

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SYNOPSIS Malaria, caused by Plasmodia parasites, affects hundreds of millions of people. As purine auxotrophs, Plasmodia use transporters to import host purines for subsequent metabolism by the purine salvage pathway. Thus, purine transporters are attractive drug targets. All sequenced Plasmodia genomes encode four Equilibrative Nucleoside Transporters (ENTs). During the pathogenic intraerythrocytic stages, ENT1 is a major route of purine nucleoside/nucleobase transport. Another plasma membrane purine transporter exists because Plasmodium falciparum ENT1-knockout parasites survive at supraphysiological purine concentrations. The other three ENTs have not been characterized functionally. Codon-optimized P. falciparum and P. vivax ENT4 were expressed in Xenopus laevis oocytes and substrate transport determined with radiolabeled substrates. ENT4 transported adenine and 2′-deoxyadenosine at the fastest rate, with millimolar-range apparent affinity. ENT4-expressing oocytes did not accumulate hypoxanthine, a key purine salvage pathway substrate, or AMP. Micromolar concentrations of the plant hormone cytokinin compounds inhibited both Pf- and Pv-ENT4. In contrast to PfENT1, ENT4 interacted with the Immucillin compounds in the millimolar range and was inhibited by 10 μM dipyridamole. Thus, ENT4 is a purine transporter with unique substrate and inhibitor specificity. Its role in parasite physiology remains uncertain but is likely significant because of the strong conservation of ENT4 homologues in Plasmodia genomes.

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Ultrastructure of Trypanosoma cruzi revisited by atomic force microscopy

Rocha

Miranda

Weissmüller

et al. 2007

Microscopy Res & Technique

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Most advances in atomic force microscopy (AFM) have been accomplished in recent years. Previous attempts to use AFM to analyze the organization of pathogenic protozoa did not significantly contribute with new structural information. In this work, we introduce a new perspective to the study of the ultrastructure of the epimastigote form of Trypanosoma cruzi by AFM. Images were compared with those obtained using field emission scanning electron microscopy of critical point dried cells and transmission electron microscopy of negative stained detergent-extracted and air-dried cells. AFM images of epimastigote forms showed a flagellum furrow separating the axoneme from the paraflagellar rod (PFR) present from the emergence of the flagellar pocket to the tip of the flagellum. At high magnification, a row of periodically organized structures, which probably correspond to the link between the axoneme, the PFR and the flagellar membrane were seen along the furrow. In the origin of the flagellum, two basal bodies were identified. Beyond the basal bodies, small periodically arranged protrusions, positioned at 400 nm from the flagellar basis were seen. This structure was formed by nine substructures distributed around the flagellar circumference and may correspond to the flagellar necklace. Altogether, our results demonstrate the importance of the application of AFM in the structural characterization of the surface components and cytoskeleton on protozoan parasites.

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Effects of dipyridamole on Plasmodium falciparum -infected erythrocytes

Cited by 11 publications

References 19 publications

PfPDE1, a novel cGMP-specific phosphodiesterase from the human malaria parasitePlasmodium falciparum

PfPDE1, a novel cGMP-specific phosphodiesterase from the human malaria parasitePlasmodium falciparum

Malaria parasite type 4 equilibrative nucleoside transporters (ENT4) are purine transporters with distinct substrate specificity

Ultrastructure of Trypanosoma cruzi revisited by atomic force microscopy

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