Copper, a transition metal with essential cellular functions, exerts neurotoxic effects when present in excess by promoting production of reactive oxygen species (ROS). The aim of the present study was to investigate potential benefits of flavonoid quercetin against copper-induced toxicity. Results obtained with MTT assay indicate that the effects of quercetin are determined by the severity of the toxic insult. In moderately injured P19 neuronal cells, concomitant treatment with 150 μM quercetin improved viability by preventing ROS formation, caspase-3 activation, and chromatin condensation. Western blot analysis revealed that quercetin reduced copper-induced increase in p53 upregulated modulator of apoptosis (PUMA) expression and promoted upregulation of nucleoside diphosphate kinase NME1. Levels of p53 and Bax proteins were not affected by both copper and quercetin. UO126 and wortmannin, inhibitors of ERK1/2 and PI3K/Akt signalling pathways, respectively, prevented neuroprotective effects of quercetin. In severely injured neurons, 30 μM quercetin exerted strong prooxidative action and exacerbated cytotoxic effects of copper, whereas 150 μM quercetin failed to affect neuronal survival. These results demonstrate the dual nature of quercetin action in copper-related neurodegeneration. Hence, they are relevant in the context of considering quercetin as a possible therapeutic for neuroprotection and imply that detailed pharmacological and toxicological studies must be carried out for natural compounds capable of acting both as antioxidants and prooxidants.

中文翻译：

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PI3K/Akt 和 ERK1/2 信号转导参与槲皮素介导的针对铜诱导损伤的神经保护作用。


铜是一种具有重要细胞功能的过渡金属，过量存在时会促进活性氧 (ROS) 的产生，从而发挥神经毒性作用。本研究的目的是研究类黄酮槲皮素对铜引起的毒性的潜在益处。 MTT 测定获得的结果表明槲皮素的作用取决于毒性损伤的严重程度。在中度损伤的 P19 神经元细胞中，同时使用 150 μM槲皮素治疗可通过防止 ROS 形成、caspase-3 激活和染色质浓缩来提高活力。蛋白质印迹分析显示，槲皮素可减少铜诱导的 p53 上调细胞凋亡调节剂 (PUMA) 表达的增加，并促进核苷二磷酸激酶 NME1 的上调。 p53 和 Bax 蛋白的水平不受铜和槲皮素的影响。 UO126 和渥曼青霉素分别是 ERK1/2 和 PI3K/Akt 信号通路的抑制剂，可阻止槲皮素的神经保护作用。在严重损伤的神经元中， 30μM槲皮素发挥强烈的促氧化作用，并加剧铜的细胞毒性作用，而150μM槲皮素未能影响神经元的存活。这些结果证明了槲皮素在铜相关神经变性中作用的双重性质。因此，它们与考虑槲皮素作为神经保护的可能治疗剂的背景相关，并且意味着必须对能够同时充当抗氧化剂和促氧化剂的天然化合物进行详细的药理学和毒理学研究。