Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
Oxid Med Cell Longev. 2019 Jun 17;2019:9693726. doi: 10.1155/2019/9693726. eCollection 2019.
Trace metals such as zinc (Zn), copper (Cu), and nickel (Ni) play important roles in various physiological functions such as immunity, cell division, and protein synthesis in a wide variety of species. However, excessive amounts of these trace metals cause disorders in various tissues of the central nervous system, respiratory system, and other vital organs. Our previous analysis focusing on neurotoxicity resulting from interactions between Zn and Cu revealed that Cu markedly enhances Zn-induced neuronal cell death by activating oxidative stress and the endoplasmic reticulum (ER) stress response. However, neurotoxicity arising from interactions between zinc and metals other than copper has not been examined. Thus, in the current study, we examined the effect of Ni on Zn-induced neurotoxicity. Initially, we found that nontoxic concentrations (0-60 M) of Ni enhance Zn-induced neurotoxicity in an immortalized hypothalamic neuronal cell line (GT1-7) in a dose-dependent manner. Next, we analyzed the mechanism enhancing neuronal cell death, focusing on the ER stress response. Our results revealed that Ni treatment significantly primed the Zn-induced ER stress response, especially expression of the CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, we examined the effect of carnosine (an endogenous peptide) on Ni/Zn-induced neurotoxicity and found that carnosine attenuated Ni/Zn-induced neuronal cell death and ER stress occurring before cell death. Based on our results, Ni treatment significantly enhances Zn-induced neuronal cell death by priming the ER stress response. Thus, compounds that decrease the ER stress response, such as carnosine, may be beneficial for neurological diseases.
痕量金属，如锌（Zn）、铜（Cu）和镍（Ni），在各种物种的各种生理功能中发挥着重要作用，如免疫、细胞分裂和蛋白质合成。然而，这些痕量金属的过量会导致中枢神经系统、呼吸系统和其他重要器官的各种组织紊乱。我们之前的分析集中在 Zn 和 Cu 相互作用引起的神经毒性上，结果表明 Cu 通过激活氧化应激和内质网（ER）应激反应显著增强了 Zn 诱导的神经元细胞死亡。然而，尚未研究锌与除铜以外的金属相互作用引起的神经毒性。因此，在本研究中，我们研究了 Ni 对 Zn 诱导的神经毒性的影响。最初，我们发现非毒性浓度（0-60μM）的 Ni 以剂量依赖性方式增强了永生下丘脑神经元细胞系（GT1-7）中 Zn 诱导的神经毒性。接下来，我们分析了增强神经元细胞死亡的机制，重点关注 ER 应激反应。我们的结果表明，Ni 处理显著引发了 Zn 诱导的 ER 应激反应，特别是 CCAAT 增强子结合蛋白同源蛋白（CHOP）的表达。最后，我们研究了肌肽（一种内源性肽）对 Ni/Zn 诱导的神经毒性的影响，发现肌肽可减轻 Ni/Zn 诱导的神经元细胞死亡和细胞死亡前发生的 ER 应激。基于我们的结果，Ni 处理通过引发 ER 应激反应显著增强了 Zn 诱导的神经元细胞死亡。因此，减少 ER 应激反应的化合物，如肌肽，可能对神经疾病有益。
