D-Histidine and L-histidine attenuate zinc-induced neuronal death in GT1-7 cells
D-Histidine and L-histidine attenuate zinc-induced neuronal death in GT1-7 cells
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DOI：
10.1039/c3mt20264j
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发表时间：
2013-01-01
期刊：
影响因子：
3.4
通讯作者：
Ohkawara, Susumu
中科院分区：
文献类型：
--
作者：
Kawahara, Masahiro;Sadakane, Yutaka;Ohkawara, Susumu
虽然锌（Zn）是一种必需的微量元素，但过量的Zn会导致短暂性全脑缺血后的神经元死亡，并在血管性痴呆的发病机制中起核心作用。在这项研究中，我们开发了一个快速和方便的筛选系统的物质，防止锌诱导的神经毒性使用GT 1 -7细胞（永生化下丘脑神经元），目的是确定治疗血管型痴呆症。在所检测的蛋白质中，我们发现了一种保护性物质，并确定其结构为L-组氨酸。组氨酸类似物的构效关系分析表明，L-组氨酸和D-组氨酸具有相同的神经保护活性。此外，我们研究了组氨酸对锌诱导的神经毒性的保护作用的分子机制，使用锌成像和基因表达分析，并发现组氨酸保护锌诱导的神经毒性，而不是通过抑制锌螯合，从而防止细胞内锌2+的增加。此外，还表明内质网（ER）应激和活性调节的细胞骨架相关蛋白（Arc）参与锌诱导的神经元变性。
Although zinc (Zn) is an essential trace element, excess Zn causes neuronal death following transient global ischemia and plays a central role in the pathogenesis of vascular-type dementia. In this study, we developed a rapid and convenient screening system for substances that prevent Zn-induced neurotoxicity by using GT1-7 cells (immortalized hypothalamic neurons), with the aim of identifying a treatment for vascular-type dementia. Among tested, we found a protective substance in the extract of round herring (Etrumeus teres), and determined its structure as L-histidine. Analysis of the structure-activity relationship by using histidine analogues revealed that both L-histidine and D-histidine exhibit the same neuroprotective activity. Furthermore, we investigated the molecular mechanisms underlying the protective effect of histidine on Zn-induced neurotoxicity using Zn imaging and gene expression analysis, and found that histidine protects against Zn-induced neurotoxicity not by inhibiting Zn chelation, thereby preventing increases in intracellular Zn2+. Moreover, it is also suggested that endoplasmic reticulum (ER) stress and activity-regulated cytoskeleton associated protein (Arc) are implicated in Zn-induced degeneration of neurons.