Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, Insurgentes Sur 3877, 14269, Ciudad de México, Mexico.
Facultad de Ciencias, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico.
Neurotox Res. 2018 Feb;33(2):259-267. doi: 10.1007/s12640-017-9794-x. Epub 2017 Aug 18.
The tryptophan metabolite, quinolinic acid (QUIN), and the mitochondrial toxin 3-nitropropionic acid (3-NP) are two important tools for toxicological research commonly used in neurotoxic models of excitotoxicity, oxidative stress, energy depletion, and neuronal cell death in mammals. However, their toxic properties have yet to be explored in the nematode Caenorhabditis elegans (C. elegans) for the establishment of novel, simpler, complementary, alternative, and predictive neurotoxic model of mammalian neurotoxicity. In this work, the effects of QUIN (1-100 mM) and 3-NP (1-10 mM) were evaluated on various physiological parameters (survival, locomotion, and longevity) in a wild-type (WT) strand of C. elegans (N2). Their effects were also tested in the VC1772 strain (knock out for the antioxidant SKN-1 pathway) and the VP596 strain (worms with a reporter gene for glutathione S-transferase (GST) transcription) in order to establish the role of the SKN-1 pathway in the mode of action of QUIN and 3-NP. In N2, the higher doses of both toxins decreased survival, though only QUIN altered motor activity. Both toxins also reduced longevity in the VC1772 strain (as compared to N2 strain) and augmented GST transcription in the VP596 strain at the highest doses. The changes induced by both toxins require high doses, and therefore appear moderate when compared with other toxic agents. Nevertheless, the alterations produced by QUIN and 3-NP in C. elegans are relevant to mammalian neurotoxicity as they provide novel mechanistic approaches to the assessment of neurotoxic events comprising oxidative stress and excitotoxicity, in the nematode model.
色氨酸代谢物喹啉酸（QUIN）和线粒体毒素 3-硝基丙酸（3-NP）是两种常用于哺乳动物兴奋性毒性、氧化应激、能量耗竭和神经元细胞死亡的神经毒性模型的毒理学研究的重要工具。然而，它们的毒性特性尚未在秀丽隐杆线虫（C. elegans）中进行研究，以建立新的、更简单、互补、替代和预测哺乳动物神经毒性的神经毒性模型。在这项工作中，评估了 QUIN（1-100 mM）和 3-NP（1-10 mM）对野生型（WT）秀丽隐杆线虫（N2）的各种生理参数（存活、运动和寿命）的影响。还在 VC1772 菌株（抗氧化剂 SKN-1 途径的敲除）和 VP596 菌株（谷胱甘肽 S-转移酶（GST）转录报告基因的线虫）中测试了它们的作用，以确定 SKN-1 途径在 QUIN 和 3-NP 作用模式中的作用。在 N2 中，两种毒素的较高剂量都降低了存活率，尽管只有 QUIN 改变了运动活性。两种毒素还降低了 VC1772 菌株（与 N2 菌株相比）的寿命，并在最高剂量下增加了 VP596 菌株中的 GST 转录。两种毒素诱导的变化需要高剂量，因此与其他毒性剂相比，它们的影响似乎适中。然而，QUIN 和 3-NP 在秀丽隐杆线虫中产生的改变与哺乳动物神经毒性有关，因为它们为评估包括氧化应激和兴奋性毒性在内的神经毒性事件提供了新的机制方法。
