Biological Sciences, Institute for Life Sciences, University of Southampton, Southampton, United Kingdom.
Biological Sciences, Institute for Life Sciences, University of Southampton, Southampton, United Kingdom.
Neurotoxicology. 2021 Jan;82:50-62. doi: 10.1016/j.neuro.2020.11.001. Epub 2020 Nov 8.
Inhibition of acetylcholinesterase by either organophosphates or carbamates causes anti-cholinesterase poisoning. This arises through a wide range of neurotoxic effects triggered by the overstimulation of the cholinergic receptors at synapses and neuromuscular junctions. Without intervention, this poisoning can lead to profound toxic effects, including death, and the incomplete efficacy of the current treatments, particularly for oxime-insensitive agents, provokes the need to find better antidotes. Here we show how the non-parasitic nematode Caenorhabditis elegans offers an excellent tool for investigating the acetylcholinesterase intoxication. The C. elegans neuromuscular junctions show a high degree of molecular and functional conservation with the cholinergic transmission that operates in the autonomic, central and neuromuscular synapses in mammals. In fact, the anti-cholinesterase intoxication of the worm's body wall neuromuscular junction has been unprecedented in understanding molecular determinants of cholinergic function in nematodes and other organisms. We extend the use of the model organism's feeding behaviour as a tool to investigate carbamate and organophosphate mode of action. We show that inhibition of the cholinergic-dependent rhythmic pumping of the pharyngeal muscle correlates with the inhibition of the acetylcholinesterase activity caused by aldicarb, paraoxons and DFP exposure. Further, this bio-assay allows one to address oxime dependent reversal of cholinesterase inhibition in the context of whole organism recovery. Interestingly, the recovery of the pharyngeal function after such anti-cholinesterase poisoning represents a sensitive and easily quantifiable phenotype that is indicative of the spontaneous recovery or irreversible modification of the worm acetylcholinesterase after inhibition. These observations highlight the pharynx of C. elegans as a new tractable approach to explore anti-cholinesterase intoxication and recovery with the potential to resolve critical genetic determinants of these neurotoxins' mode of action.
乙酰胆碱酯酶被有机磷或氨基甲酸酯抑制会导致抗胆碱酯酶中毒。这是由于在突触和神经肌肉接头处，胆碱能受体过度刺激引发了广泛的神经毒性作用。如果不进行干预，这种中毒会导致严重的毒性作用，包括死亡，而且目前治疗方法的效果并不完全，特别是对于肟类不敏感的药物，这促使人们需要寻找更好的解毒剂。在这里，我们展示了非寄生线虫秀丽隐杆线虫如何成为研究乙酰胆碱酯酶中毒的极好工具。秀丽隐杆线虫的神经肌肉接头在分子和功能上与在哺乳动物自主、中枢和神经肌肉突触中起作用的胆碱能传递高度保守。事实上，蠕虫体壁神经肌肉接头的抗胆碱酯酶中毒在理解线虫和其他生物体中胆碱能功能的分子决定因素方面是前所未有的。我们扩展了该模型生物摄食行为的用途，将其作为一种工具来研究氨基甲酸酯和有机磷的作用方式。我们表明，抑制胆碱能依赖性的咽肌有节奏的抽吸与在 aldicarb、paraoxon 和 DFP 暴露下抑制乙酰胆碱酯酶活性相关。此外，这种生物测定法可以用于研究肟类依赖的胆碱酯酶抑制在整个生物体恢复中的逆转。有趣的是，在这种抗胆碱酯酶中毒后，咽功能的恢复代表了一个敏感且易于量化的表型，表明蠕虫乙酰胆碱酯酶在抑制后自发恢复或不可逆修饰。这些观察结果突出了秀丽隐杆线虫的咽作为一种新的可处理方法，用于探索抗胆碱酯酶中毒和恢复，具有解决这些神经毒素作用方式的关键遗传决定因素的潜力。
