García-Aguilar Rosario, Ortega Arturo, López-Bayghen Esther, Ramírez-Martínez Leticia, Rodriguez-Campuzano Ada, Murillo-González Fátima, Elizondo Guillermo, Vega Libia
Department of Toxicology, Center for Research and Advanced Studies of the National Polytechnic Institute, Mexico City, Mexico.
Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute, Mexico City, Mexico.
Neurotoxicology. 2023 Dec;99:282-291. doi: 10.1016/j.neuro.2023.11.007. Epub 2023 Nov 17.
Rotenone is a pesticide commonly used in agriculture that is associated with the risk of developing Parkinson's disease (PD) by inducing mitochondrial damage. As a protective cell response to different challenges, they activate mitophagy, which involves parkin activity. Parkin is an E3 ubiquitin ligase necessary in the initial steps of mitophagy, and its overexpression protects against parkinsonian effects in different models. Recent studies have reported that the aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor, induces parkin expression. Kynurenine, an endogenous AHR ligand, promotes neuroprotection in chronic neurodegenerative disorders, such as PD, although its neuroprotective mechanism needs to be fully understood. Therefore, we evaluated whether the overexpression of parkin by AHR activation with kynurenine promotes autophagy and reduces the neurotoxicity induced by rotenone in SH-SY5Y cells differentiated to dopaminergic neurons. SH-SY5Y neurons were treated with rotenone or pretreated with kynurenine or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and parkin levels, apoptosis, mitochondrial potential membrane, and autophagy were determined. The results showed that kynurenine and TCDD treatments induced parkin expression in an AHR-dependent manner. Kynurenine pretreatment inhibited rotenone-induced neuronal apoptosis in 17%, and the loss of mitochondrial membrane potential in 30% when compare to rotenone alone, together with a decrease in autophagy. By contrast, although TCDD treatment increased parkin levels, non-neuroprotective effects were observed. The kynurenine protective activity was AHR independent, suggesting that parkin induction might not be related to this effect. On the other hand, kynurenine treatment inhibited alpha amine-3-hydroxy-5-methyl-4-isoxazol propionic acid and N-methyl-D-aspartate receptors, which are well-known excitotoxicity mediators activated by rotenone exposure.
鱼藤酮是一种常用于农业的杀虫剂，它通过诱导线粒体损伤与帕金森病（PD）的发病风险相关。作为对不同挑战的一种保护性细胞反应，细胞会激活线粒体自噬，这涉及帕金蛋白的活性。帕金蛋白是线粒体自噬初始步骤中必需的一种E3泛素连接酶，其过表达在不同模型中可预防帕金森病效应。最近的研究报道，芳烃受体（AHR），一种配体依赖性转录因子，可诱导帕金蛋白表达。犬尿氨酸，一种内源性AHR配体，在慢性神经退行性疾病如PD中促进神经保护作用，尽管其神经保护机制尚需充分了解。因此，我们评估了用犬尿氨酸激活AHR使帕金蛋白过表达是否能促进自噬并降低鱼藤酮在分化为多巴胺能神经元的SH-SY5Y细胞中诱导的神经毒性。用鱼藤酮处理SH-SY5Y神经元，或先用犬尿氨酸或2,3,7,8-四氯二苯并对二恶英（TCDD）预处理，然后测定帕金蛋白水平、细胞凋亡、线粒体膜电位和自噬情况。结果表明，犬尿氨酸和TCDD处理以AHR依赖性方式诱导帕金蛋白表达。与单独使用鱼藤酮相比，犬尿氨酸预处理可抑制鱼藤酮诱导的17%的神经元凋亡和30%的线粒体膜电位丧失，同时自噬减少。相比之下，尽管TCDD处理增加了帕金蛋白水平，但未观察到神经保护作用。犬尿氨酸的保护活性不依赖于AHR，这表明帕金蛋白的诱导可能与这种效应无关。另一方面，犬尿氨酸处理可抑制α-氨基-3-羟基-5-甲基-4-异恶唑丙酸和N-甲基-D-天冬氨酸受体，这两种受体是鱼藤酮暴露激活的众所周知的兴奋性毒性介质。
