Proanthocyanidins inhibit Ascaris suum glutathione-S-transferase activity and increase susceptibility of larvae to levamisole in vitro.
Proanthocyanidins (PAC) are a class of plant secondary metabolites commonly found in the diet that have shown potential to control gastrointestinal nematode infections. The anti-parasitic mechanism(s) of PAC remain obscure, however the protein-binding properties of PAC suggest that disturbance of key enzyme functions may be a potential mode of action. Glutathione-S-transferases (GSTs) are essential for parasite detoxification and have been investigated as drug and vaccine targets. Here, we show that purified PAC strongly inhibit the activity of both recombinant and native GSTs from the parasitic nematode Ascaris suum. As GSTs are involved in detoxifying xenobiotic substances within the parasite, we hypothesised that this inhibition may render parasites hyper-susceptible to anthelmintic drugs. Migration inhibition assays with A. suum larvae demonstrated that the potency of levamisole (LEV) and ivermectin (IVM) were significantly increased in the presence of PAC purified from pine bark (4.6-fold and 3.2-fold reduction in IC50 value for LEV and IVM, respectively). Synergy analysis revealed that the relationship between PAC and LEV appeared to be synergistic in nature, suggesting a specific enhancement of LEV activity, whilst the relationship between PAC and IVM was additive rather than synergistic, suggesting independent actions. Our results demonstrate that these common dietary compounds may increase the efficacy of synthetic anthelmintic drugs in vitro, and also suggest one possible mechanism for their well-known anti-parasitic activity.
Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
Tina V A
TV
Hansen
Chemistry and Biochemistry Laboratory, School of Agriculture, Policy and Development, University of Reading, Reading, United Kingdom.
Christos
C
Fryganas
Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.
Nathalie
N
Acevedo
Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.
Luis
L
Caraballo
Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
Stig M
SM
Thamsborg
Chemistry and Biochemistry Laboratory, School of Agriculture, Policy and Development, University of Reading, Reading, United Kingdom.
Irene
I
Mueller-Harvey
Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark. Electronic address: arw@sund.ku.dk.
Andrew R
AR
Williams
D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001196:Ascariasis / Q000188:drug therapy* / Q000469:parasitology; D017165:Ascaris suum / Q000166:cytology / Q000187:drug effects*; D004357:Drug Synergism; D035264:Flowers / Q000737:chemistry; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015801:Helminth Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007559:Ivermectin / Q000494:pharmacology; D007814:Larva; D007978:Levamisole / Q000494:pharmacology; D041605:Pinus sylvestris / Q000737:chemistry*; D024301:Plant Bark / Q000737:chemistry; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D044945:Proanthocyanidins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D029921:Trifolium / Q000737:chemistry*
D000871:Anthelmintics; D015801:Helminth Proteins; D010936:Plant Extracts; D044945:Proanthocyanidins; D007978:Levamisole; D007559:Ivermectin; D005982:Glutathione Transferase