Parasitic nematodes plague the world as major contributors to disease, and anti-parasitic drugs (anthelmintics) are the primary control measure. New chemotherapeutic agents or improvements in currently used agents are needed because parasitic helminths continue to develop resistance against current medications. Discovery and/or validation of new anthelmintic agents as well as improvement of currently used drugs require a thorough understanding of the efficacy of these agents, their specific targets and mechanisms of action. Most anthelmintics target the locomotory system and either directly or indirectly compromise the ability of nematodes to move and remain in the host. Previous work has focused on anthelmintic effects on nematode muscle. Unfortunately, little is known about the effects of anthelmintics or potential anthelmintics on the nervous system (which controls locomotory behavior), because studying the neurophysiology of nematode nerve cells has been extremely difficult. The proposed research will make use of my lab's ability to directly record from nematode neurons and will use electro-physiological and neuropharmacological techniques. The overall goal is to determine neuronal targets and mechanisms of action for promising new agents that might ultimately be added to our chemotherapeutic arsenal as well as to explore in more depth the possible targets and mechanisms of action of two very widely used anthelmintics. Using the parasitic nematode Ascaris suum, we will assess the following agents: PF1022A, nitazoxanide and its metabolite tizoxanide, bombesin, two opioid-related alkaloids, paraherquamide, ivermectin and albendazole. The neurophysiological responses that will be studied include: spontaneous and evoked changes in electrical activity, changes in neuronal signaling capabilities, and effects on synaptic transmission to muscles and other neurons in the locomotory circuit. ?
The proposed research will help to delineate or refine anti-parasitic agents, their targets and mechanisms of action in the nematode nervous system. This work is driven by the hypothesis that the agents to be studied compromise the function of the parasite's neuromuscular system; preliminary evidence supports this hypothesis for the agents to be studied. This work is a combination of basic and translational research which will further our efforts to develop effective anti-parasitic medications. ? ? ?
