Institute of Parasitology, McGill University, Macdonald Campus, 21, 111 Lakeshore Road, Ste Anne de Bellevue, Quebec, Canada H9X-3V9
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
Dis Model Mech. 2018 Jul 30;11(7):dmm033563. doi: 10.1242/dmm.033563.
Schistosomiasis is a tropical disease caused by a flatworm trematode parasite that infects over 200 million people worldwide. Treatment and control of the disease rely on just one drug, praziquantel. The possibility of drug resistance coupled with praziquantel's variable efficacy encourages the identification of new drugs and drug targets. Disruption of neuromuscular homeostasis in parasitic worms is a validated strategy for drug development. In schistosomes, however, much remains to be understood about the organization of the nervous system, its component neurotransmitters and potential for drug discovery. Using synapsin as a neuronal marker, we map the central and peripheral nervous systems in the adult and schistosomulum (post-infective larva). We discover the widespread presence of octopamine (OA), a tyrosine-derived and invertebrate-specific neurotransmitter involved in neuromuscular coordination. OA labeling facilitated the discovery of two pairs of ganglia in the brain of the adult schistosome, rather than the one pair thus far reported for this and other trematodes. In quantitative phenotypic assays, OA and the structurally related tyrosine-derived phenolamine and catecholamine neurotransmitters differentially modulated schistosomulum motility and length Similarly, from a screen of 28 drug agonists and antagonists of tyrosine-derivative signaling, certain drugs that act on OA and dopamine receptors induced robust and sometimes complex concentration-dependent effects on schistosome motility and length; in some cases, these effects occurred at concentrations achievable The present data advance our knowledge of the organization of the nervous system in this globally important pathogen and identify a number of drugs that interfere with tyrosine-derivative signaling, one or more of which might provide the basis for a new chemotherapeutic approach to treat schistosomiasis.This article has an associated First Person interview with the first author of the paper.
血吸虫病是一种由扁形动物吸虫寄生虫引起的热带病，全球有超过 2 亿人感染。该疾病的治疗和控制依赖于一种药物，即吡喹酮。药物耐药性的可能性以及吡喹酮疗效的可变性鼓励人们寻找新的药物和药物靶点。破坏寄生虫的神经肌肉平衡是药物开发的一种有效策略。然而，在血吸虫中，对于神经系统的组织、其组成神经递质以及药物发现的潜力，仍有许多需要了解的地方。我们使用突触结合蛋白作为神经元标记，绘制了成虫和尾蚴（感染后幼虫）的中枢和外周神经系统图谱。我们发现章鱼胺（OA）广泛存在，OA 是一种酪氨酸衍生的、无脊椎动物特有的神经递质，参与神经肌肉协调。OA 标记有助于在成虫血吸虫的大脑中发现两对神经节，而不是迄今为止为此和其他吸虫报告的一对。在定量表型测定中，OA 以及结构上相关的酪氨酸衍生的酚胺和儿茶酚胺神经递质差异调节尾蚴的运动和长度。同样，从 28 种酪氨酸衍生信号的药物激动剂和拮抗剂筛选中，某些作用于 OA 和多巴胺受体的药物对尾蚴的运动和长度产生了强烈且有时复杂的浓度依赖性影响；在某些情况下，这些作用发生在可达到的浓度下。目前的数据增进了我们对这种在全球范围内重要病原体的神经系统组织的认识，并确定了一些干扰酪氨酸衍生信号的药物，其中一种或多种药物可能为治疗血吸虫病提供新的化学治疗方法。本文附有该论文第一作者的第一人称采访。
