Modulation of levamisole receptors: Pharmacological Diversity of Clade III nAChRs

Iowa State University, Ames IA

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Abstract

Project Summary 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 and is caused by filarial nematodes like Brugia malayi. Control of these nematode parasites 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 more basic science that will facilitate the use of existing drugs and the development of new drugs. 2. Recently, several novel nematode selective cholinergic anthelmintics, including tribendimidine and derquantel, have been introduced and increased the significance of cholinergic anthelmintics. Tribendimidine has potential for single-dose Mass Drug Administration. Derquantel has [unreadable]resistance busting[unreadable] 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 nAChR, referred to as the levamisole receptor, is divided into N-, L- and B-subtypes in the Clade III nematode Ascaris suum. The pharmacology of Clade III levamisole receptors may be plastic and modulated by receptor subunit stoichiometry. The therapeutic importance of the subtypes and the modulation demands further investigation in parasitic nematodes. We have three aims. 3. Our approach will use muscle contraction assays, current-clamp, voltage-clamp, patchclamp, cloning &Xenopus oocyte expression and pharmacological agents, to distinguish the subtypes. Aim #1 will test the hypothesis that tribendimidine is or is not an nAChR agonist that is either N-, L- or B-subtype selective in A. suum and if it is an open-channel blocker. Aim #2 will express specific nicotinic receptor subunits from A. suum in different combinations to test the hypothesis that modulation of subunit stoichiometry reproduces the pharmacological diversity of native 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 modulatory, plastic and important pharmacological properties of Clade III nAChRs and extending, 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 &logical use of tribendimidine, a potential single-dose MDA;a significant impact on understanding of modulation &pharmacological diversity of nicotinic anthelmintic target sites in Clade III nematodes;a powerful influence on development of a novel B. malayi preparation for studying ion-channel drug targets;new knowledge allowing development of improved anthelmintic combinations of nAChR receptor subtype selective drugs.