Abstract
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 dose-dependent 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.
Highlights
The 4 major human gastrointestinal (GI) nematodes, Ascaris lumbricoides, Trichuris trichiura, Ancylostoma duodenale and Necator americanus, infect millions of people throughout the world
In order to determine the efficacy of crude papaya latex against intestinal nematodes in vivo, we administered papaya latex daily for 7 days (133 nmol active cysteine proteinase/mouse at each treatment), from days 18–24 post-infection, to 5 male C3H mice which had been infected with 200 L3 of H. polygyrus on day 0
These results clearly demonstrate the anthelmintic efficacy of papaya latex, and show that worms are lost over several days as treatment is sustained daily
Summary
The 4 major human gastrointestinal (GI) nematodes, Ascaris lumbricoides, Trichuris trichiura, Ancylostoma duodenale and Necator americanus, infect millions of people throughout the world. These parasites rarely cause acute infections, the resulting chronic infections are serious and produce a greater burden on life (39.0 million DALYs ; DALYs= disability-adjusted life years) than, for example, malaria (35.6 million DALYs) (Chan, 1997 ; Molyneux et al 2005). There is an urgent need for the Parasitology (2007), 134, 1409–1419. f 2007 Cambridge University Press doi:10.1017/S0031182007002867 Printed in the United Kingdom
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