Institute of Toxicology, Medical Faculty, Heinrich Heine University, D-40225 Düsseldorf, Germany.
Faculty of Mathematics and Natural Sciences, Food Chemistry, University of Wuppertal, D-42119 Wuppertal, Germany.
Pharmacol Res. 2021 Dec;174:105921. doi: 10.1016/j.phrs.2021.105921. Epub 2021 Oct 1.
Neurotoxicity is a frequent side effect of cisplatin (CisPt)-based anticancer therapy whose pathophysiology is largely vague. Here, we exploited C. elegans as a 3R-compliant in vivo model to elucidate molecular mechanisms contributing to CisPt-induced neuronal dysfunction. To this end, we monitored the impact of CisPt on various sensory functions as well as pharyngeal neurotransmission by recording electropharyngeograms (EPGs). CisPt neither affected food and odor sensation nor mechano-sensation, which involve dopaminergic and glutaminergic neurotransmission. However, CisPt reduced serotonin-regulated pharyngeal pumping activity independent of changes in the morphology of related neurons. CisPt-mediated alterations in EPGs were fully rescued by addition of serotonin (5-HT) (≤ 2 mM). Moreover, the CisPt-induced pharyngeal injury was prevented by co-incubation with the clinically approved serotonin re-uptake inhibitory drug duloxetine. A protective effect of 5-HT was also observed with respect to CisPt-mediated impairment of another 5-HT-dependent process, the egg laying activity. Importantly, CisPt-induced apoptosis in the gonad and learning disability were not influenced by 5-HT. Using different C. elegans mutants we found that CisPt-mediated (neuro)toxicity is independent of serotonin biosynthesis and re-uptake and likely involves serotonin-receptor subtype 7 (SER-7)-related functions. In conclusion, by measuring EPGs as a surrogate parameter of neuronal dysfunction, we provide first evidence that CisPt-induced neurotoxicity in C. elegans involves 5-HT-dependent neurotransmission and SER-7-mediated signaling mechanisms and can be prevented by the clinically approved antidepressant duloxetine. The data highlight the particular suitability of C. elegans as a 3R-conform in vivo model in molecular (neuro)toxicology and, moreover, for the pre-clinical identification of neuroprotective candidate drugs.
神经毒性是顺铂（CisPt）为基础的抗癌治疗的常见副作用，其病理生理学在很大程度上尚不清楚。在这里，我们利用秀丽隐杆线虫作为符合 3R 原则的体内模型，阐明导致 CisPt 诱导的神经元功能障碍的分子机制。为此，我们通过记录电咽图（EPG）来监测 CisPt 对各种感觉功能以及咽神经传递的影响。CisPt 既不影响食物和气味感觉，也不影响机械感觉，而这些感觉涉及多巴胺能和谷氨酰胺能神经传递。然而，CisPt 降低了与相关神经元形态变化无关的 5-羟色胺调节的咽泵活动。CisPt 介导的 EPG 变化可通过添加 5-羟色胺（5-HT）（≤2 mM）完全挽救。此外，与临床批准的 5-羟色胺再摄取抑制药物度洛西汀共孵育可预防 CisPt 诱导的咽损伤。5-HT 还观察到对 CisPt 介导的另一种 5-HT 依赖性过程，即产卵活性的损伤的保护作用。重要的是，5-HT 对 CisPt 诱导的性腺凋亡和学习障碍没有影响。使用不同的秀丽隐杆线虫突变体，我们发现 CisPt 介导的（神经）毒性独立于 5-羟色胺的生物合成和再摄取，可能涉及 5-羟色胺受体亚型 7（SER-7）相关功能。总之，通过测量 EPG 作为神经元功能障碍的替代参数，我们提供了第一个证据，表明 CisPt 在秀丽隐杆线虫中诱导的神经毒性涉及 5-HT 依赖性神经传递和 SER-7 介导的信号机制，并且可以通过临床批准的抗抑郁药度洛西汀来预防。该数据突出了秀丽隐杆线虫作为符合 3R 原则的体内模型在分子（神经）毒理学中的特殊适用性，并且可以用于神经保护候选药物的临床前鉴定。
