1. The Neglected Tropical Diseases include ascariasis and lymphatic filariasis. These diseases are caused by parasitic nematodes that are grouped in Clade III because of their molecular similarities. Ascariasis is caused by the large intestinal roundworm, Ascaris lumbricoides. Worldwide, it occurs in 1.4 billion people. Lymphatic filariasis (elephantiasis) threatens over a billion people in 83 countries;it is caused by filaria nematodes like Brugia malayi. Control of these nematode parasites (adults or larvae) relies on a limited number of anthelmintic drugs. There are concerns that mass chemotherapy will lead to the development of resistance. There is a significant and urgent need for research that will allow better use of existing drugs, including combinations, to preserve their value, and to develop new drugs. 2. Recently, several novel nematode selective cholinergic anthelmintics, like tribendimidine and derquantel (now synergized with abamectin), have been introduced and increased the significance of cholinergic anthelmintics. Tribendimidine has potential for single-dose Mass Drug Administration. Derquantel has 'resistance busting'actions against worms that are resistant to other cholinergic anthelmintics. The pharmacology of nematode nicotinic receptors (nAChRs) is more complex than has been appreciated. The muscle nAChRs are divided into N-, L- and B-subtypes in the Clade III nematode Ascaris suum. The pharmacology of Clade III muscle receptors (levamisole receptors) are modulated by receptor subunit composition. The therapeutic importance of subtypes and modulation demands further investigation in parasitic nematodes. We have three aims. 3. Our approach will use muscle contraction assays, current-clamp, voltage-clamp, patch- clamp, cloning &Xenopus oocyte expression and pharmacological agents, to characterize actions of cholinergic anthelmintics and the subtypes of their receptors.
Aim #1 will characterize the mode of action and subtype selectivity of tribendimidine in A. suum. It will test the hypothesis that tribendimidine is not selective for the L-subtype of nAChR but another type in A. suum and determine if its action as an open-channel blocker limits efficacy.
Aim #2 will examine the effects of subunit arrangements and stoichiometry on pharmacology of Ascaris nAChRs. It will express four specific nicotinic receptor subunits from A. suum in different combinations to test the hypothesis that different subunit compositions reproduce the pharmacological diversity of native muscle receptors (levamisole receptors).
Aim #3 will characterize nAChR responses and receptors in B. malayi, to test the hypothesis that the subtypes are functionally similar to the Clade III nematode, A. suum. 4. The proposal is innovative, exploring unknown drug effects and effects of subunit arrangements on the pharmacological properties of Clade III nAChRs. We also extend, to the Brugia malayi parasite preparation, the methods that this group of investigators has developed. 5. The overall impact will be a powerful influence on: expansion &informed use of tribendimidine, a potential single-dose MDA; the expansion and informed use of the pharmacological diversity of nicotinic anthelmintic target sites in Clade III nematodes;use of a novel B. malayi preparation for studying ion-channel targets for future drug development; development or informed use of combinations (e.g. derquantel with avermectins;or combinations of subtype selective cholinergic anthelmintics).
Ascaris lumbricoides affects 1.4 billion people worldwide and Brugia malayi affects 120 million people worldwide. A limited number of anthelmintic drugs control these Clade III nematode parasites, and there is a concern about the development of resistance. We will study the pharmacological diversity of Clade III nAChRs muscle receptors involved in transmission in order to determine: 1) the subtype selectivity and channel block action of a new drug, tribendimidine;2) how pharmacological diversity of muscle receptors, including effects of derquantel and macrocyclic lactones, is modulated by subunit composition in the Xenopus oocyte expression system and;3) the nAChR subtypes present in Brugia. The outcome will include new therapeutically important information about actions of drugs that act on nAChRs and interact in combinations.
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