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

nf - e2相关因子-2 （Nrf2）是一种基本的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通路激活的化合物可能成为与氧化应激相关的神经退行性疾病的有用治疗药物。阿波啡（Apomorphine, Apo）是一种多巴胺D_1/D_2受体激动剂，是已知的抗氧化剂。在这项研究中，我们已经证明了载脂蛋白不仅作为抗氧化剂的功能，而且作为Nrf2-ARE通路激活剂的功能可能参与了载脂蛋白对氧化应激诱导的神经元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必不可少的一种离子。然而，有报道称锌可能导致神经元细胞死亡。在本研究中，我们研究了载脂蛋白是否对锌诱导的神经元细胞死亡具有保护作用。经Apo预处理的皮质神经元对锌诱导的神经元细胞死亡具有保护作用多巴胺受体拮抗剂的存在不影响保护作用。虽然锌暴露于皮质神经元诱导了BH3-only蛋白PUMA的表达，并被证明促进细胞凋亡，但载脂蛋白预处理抑制了PUMA的诱导。载脂蛋白对锌毒性的保护机制尚不清楚。因此，需要进一步的研究来了解其机制。吡咯喹啉醌（PQQ）是一种必需营养素，已被证明具有抗氧化作用。在这项研究中，我们研究了PQQ对6-羟基多巴胺（6-OHDA）诱导的人神经母细胞瘤SH-SY5Y的神经毒性的保护能力。当SH-SY5Y细胞在PQQ存在的情况下暴露于6-0HDA时，PQQ可以阻止6- ohda诱导的细胞死亡和DNA断裂。流式细胞术分析显示PQQ降低了6- ohda诱导的细胞内ROS的升高（Neuorchem Res 32,489-495,2007）。虽然我们也检查了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。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