Mechanism of zinc-induced neuronal cell death and development of neuroprotective drugs

核因子-E2相关因子-2(Nrf2)是一种碱性亮氨酸拉链转录因子，通过抗氧化反应元件(ARE)参与多种解毒和抗氧化基因的表达。最近，越来越多的证据表明，刺激NRF2-ARE途径激活的化合物可能成为治疗与氧化应激相关的神经退行性疾病的有用药物。阿朴吗啡(Apo)是一种多巴胺D_1/D_2受体激动剂，具有抗氧化作用。在这项研究中，我们证明了载脂蛋白不仅作为一种抗氧化剂的功能，而且作为一种Nrf2-ARE途径激活物的功能可能参与了载脂蛋白对氧化应激诱导的神经细胞死亡的神经保护作用(J Neurosci Res 84,860-866,2006)。锌是哺乳动物细胞中的一种必需离子。然而，有报道称锌可能与神经细胞死亡有关。在本研究中，我们研究了载脂蛋白对锌诱导的神经细胞死亡是否具有保护作用。…前处理APO对锌诱导的神经细胞死亡有更多的保护作用。在多巴胺受体拮抗剂存在的情况下，保护作用不受影响。虽然锌暴露于皮质神经元诱导了BH3-Only蛋白PUMA的表达，但APO预处理抑制了PUMA的诱导。载脂蛋白对锌中毒的保护作用机制尚不清楚。因此，还需要进一步的研究来了解其机制。吡咯喹啉醌(PQQ)是一种重要的营养物质，已被证明具有抗氧化作用。在本研究中，我们利用人神经母细胞瘤SH-SY5Y研究了PQQ对6-羟基多巴胺(6-OHDA)诱导的神经毒性的保护作用。当6-0HDA与PQQ共同作用于SH-SY5Y细胞时，PQQ可阻止6-OHDA诱导的细胞死亡和DNA断裂。流式细胞仪分析显示，PQQ降低了6-OHDA诱导的细胞内ROS的升高(Neuorchem res 32,489-495,2007)。虽然我们也研究了PQQ是否对锌诱导的细胞死亡有保护作用，但PQQ没有保护作用。较少

NF-E2-related factor-2 (Nrf2), a basic leucine zipper transcription factor, is involved in the expression of numerous detoxifying and antioxidant genes via the antioxidant response element (ARE). Recently, there is increasing evidence that compounds that stimulate the activation of the Nrf2-ARE pathway may become useful therapeutic drugs for neurodegenerative diseases associated with oxidative stress. Apomorphine (Apo), a dopamine D_1/D_2 receptor agonist, is known to be an antioxidant. In this study, we have demonstrated that not only the function as an antioxidant, but also the function as an Nrf2-ARE pathway activator may be involved in the neuroprotective effects of Apo on oxidative stress-induced neuronal cell death (J Neurosci Res 84,860-866,2006).Zinc is an essential ion in mammalian cells. However, it has been reported that zinc may contribute to neuronal cell death. In this study, we investigated whether Apo had protective effects on zinc-induced neuronal cell death. Pretreatm … More ent of cortical neurons with Apo protected against zinc-induced neuronal cell death. The protective effects were not affected in the presence of dopamine receptor antagonists. Although the exposure of zinc to cortical neurons induced the expression of the BH3-only protein PUMA, which is shown to promote apoptosis, the pretreatment with Apo suppressed the induction of PUMA. The mechanism underlying Apo protection against zinc toxicity is not clear. Therefore, future studies are required to understand the mechanism.Pyrroloquinoline quinone (PQQ), which is an essential nutrient, has been shown to act as an antioxidant. In this study, we investigated the ability of PQQ to protect against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity using human neuroblastoma SH-SY5Y. When SH-SY5Y cells were exposed to 6-0HDA in the presence of PQQ,PQQ prevented 6-OHDA-induced cell death and DNA fragmentation. Flow cytometry analysis revealed that PQQ reduced elevation of 6-OHDA-induced intracellular ROS (Neuorchem Res 32,489-495,2007). Although we also examined whether PQQ protected against zinc-induced cell death, PQQ had no protective effect. Less