Neurophysiological and Neuropharmacological Studies of a Parasitic Nematode

描述（申请人提供）：寄生线虫是危害世界的主要疾病，抗寄生虫药物（驱虫药）是主要的防治措施。需要新的化疗药物或改进目前使用的药物，因为寄生蠕虫继续对目前的药物产生耐药性。发现和/或验证新的驱虫药以及改进目前使用的药物需要彻底了解这些药物的功效，它们的特定靶点和作用机制。大多数驱虫药以运动系统为目标，直接或间接地损害线虫在宿主体内移动和停留的能力。以前的工作主要集中在驱虫对线虫肌肉的影响上。不幸的是，人们对驱虫药或潜在的驱虫药对神经系统（控制运动行为）的影响知之甚少，因为研究线虫神经细胞的神经生理学一直非常困难。拟议的研究将利用我的实验室直接记录线虫神经元的能力，并将使用电生理学和神经药理学技术。总体目标是确定有希望的新药物的神经元靶点和作用机制，这些药物最终可能被添加到我们的化疗武器库中，并更深入地探索两种广泛使用的驱虫药的可能靶点和作用机制。以猪蛔虫为研究对象，对PF1022A、硝唑尼特及其代谢物替唑尼特、bombesin、两种阿片相关生物碱、对苯二甲酸乙酯、伊维菌素和阿苯达唑等药物进行评价。将研究的神经生理反应包括：自发和诱发的电活动变化，神经元信号能力的变化，以及对运动回路中肌肉和其他神经元突触传递的影响。

DESCRIPTION (provided by applicant): 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. RELEVANCE: 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.