The anthelmintic efficacy of plant-derived cysteine proteinases against the rodent gastrointestinal nematode,Heligmosomoides polygyrus,in vivo

Abstract

A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.ukThe anthelmintic efficacy of plant-derived cysteine proteinases against the rodent gastrointestinal nematode, Heligmosomoides polygyrus, in vivo Gastrointestinal (GI) nematodes are important disease-causing organisms, controlled primarily through treatment with synthetic drugs, but the efficacy of these drugs has declined due to widespread resistance, and hence new drugs, with different modes of action, are required. Some medicinal plants, used traditionally for the treatment of worm infections, contain cysteine proteinases known to damage worms irreversibly in vitro. Here we (i) confirm that papaya latex has marked efficacy in vivo against the rodent gastrointestinal nematode, Heligmosomoides polygyrus, (ii) demonstrate the dosedependent nature of the activity (>90 % reduction in egg output and 80 % reduction in worm burden at the highest active enzyme concentration of 133 nmol), (iii) establish unequivocally that it is the cysteine proteinases that are the active principles in vivo (complete inhibition of enzyme activity when pre-incubated with the cysteine proteinase-specific inhibitor, E-64) and (iv) show that activity is confined to worms that are in the intestinal lumen. The mechanism of action was distinct from all current synthetic anthelmintics, and was the same as that in vitro, with the enzymes attacking and digesting the protective cuticle. Treatment had no detectable side-effects on immune cell numbers in the mucosa (there was no difference in the numbers of mast cells and goblet cells between the treated groups) and mucosal architecture (length of intestinal villi). Only the infected and untreated mice had much shorter villi than the other 3 groups, which was a consequence of infection and not treatment. Plant-derived cysteine proteinases are therefore prime candidates for development as novel drugs for the treatment of GI nematode infections.

Bacillus thuringiensis Cry5B Protein Is Highly Efficacious as a Single-Dose Therapy against an Intestinal Roundworm Infection in Mice

“…A single-dose administration of papaya latex at 8 g/kg achieved an efficacy of 84.5%, with fecal egg count reductions of 93.3% [42]. Mice treated daily over 7 days with 133 nmoles of papaya latex showed a decrease in fecal egg count of 87–97% and a 92% reduction of worm burden [43]. In general, few of the natural compounds tested above proved to be practical treatments due to dosing and toxicity issues.…”

Enzymology of the nematode cuticle: A potential drug target?

“…H. polygyrus adult worms were expelled rapidly within 4 h of treatment if they were damaged, resulting in a decrease in faecal egg count by 87–97% and a decrease in worm burden by 92%, suggesting that cysteine proteases from plants may be a candidate for novel anthelmintics. However, this treatment has no effect against the development of mucosal-dwelling L3 and L4 stages, only the adults in the gut lumen (Stepek et al, 2007b). Proteases from nematophagous bacteria and fungi can penetrate the cuticle of plant parasitic nematodes, causing infection of the nematode (Tian et al, 2009).…”

The anthelmintic efficacy of papaya latex in a rodent–nematode model is not dependent on fasting before treatment

“…Therefore, the current protocol, based on a refined extract of the active enzyme compartment of PL and less intervention (in that only three doses with less active enzyme content/ dose were given), achieved comparable efficacy to that observed previously with seven doses (Stepek et al, 2007b). This is likely to be beneficial for the wellbeing of the treated animals, reducing stress and the likelihood of side-effects.…”