Tungkum Wanida, Jumnongprakhon Pichaya, Tocharus Chainarong, Govitrapong Piyarat, Tocharus Jiraporn
Department of Biochemistry, Faculty of Medical Science Naresuan University, Thailand.
J Toxicol Sci. 2017;42(1):63-71. doi: 10.2131/jts.42.63.
Methamphetamine (METH) is a neurotoxic drug that causes brain damage by inducing neuronal and glial cell death together with glial cell hyperactivity-mediated progressive neurodegeneration. Previous studies have shown that METH induced glial cell hyperactivity and death via oxidative stress, the inflammatory response, and endoplasmic reticulum stress (ER stress) mechanisms, and melatonin could reverse these effects. However, the exact mechanism of the protective role of melatonin in METH-mediated ER stress has not been understood. This study investigated the protective effect of melatonin against METH toxicity-mediated ER stress in glial cells. Our study demonstrated that METH increased glial cell toxicity related to METH-induced ER stress by stimulating the unfolded protein response (UPR) to activate the expression of ER stress transducers, including phosphorylated double-stranded RNA-activated protein kinase (PKR)-like ER kinase (p-PERK), activating transcription factor (ATF6), and phosphorylated inositol-requiring enzyme 1 (p-IRE1). Moreover, the expression of binding immunoglobulin protein (Bip), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, phosphorylated eukaryotic translation initiation factor 2 alpha (p-eIF2α) and spliced X-box-binding protein-1 (XBP-1) mRNA were also increased. Melatonin reduced ER stress induced by METH toxicity by reducing the expression of ER stress response genes and proteins in a concentration-dependent manner. In addition, melatonin promoted the expression of Bip chaperone in a concentration-dependent manner. Taken together, our findings suggest that melatonin can protect against ER stress-induced glial cell death induced by METH.
甲基苯丙胺（METH）是一种神经毒性药物，通过诱导神经元和神经胶质细胞死亡以及神经胶质细胞过度活跃介导的进行性神经退行性变导致脑损伤。先前的研究表明，METH通过氧化应激、炎症反应和内质网应激（ER应激）机制诱导神经胶质细胞过度活跃和死亡，而褪黑素可以逆转这些效应。然而，褪黑素在METH介导的ER应激中的保护作用的确切机制尚不清楚。本研究调查了褪黑素对METH毒性介导的神经胶质细胞ER应激的保护作用。我们的研究表明，METH通过刺激未折叠蛋白反应（UPR）以激活ER应激转导因子的表达，包括磷酸化双链RNA激活蛋白激酶（PKR）样ER激酶（p-PERK）、激活转录因子（ATF6）和磷酸化肌醇需求酶1（p-IRE1），增加了与METH诱导的ER应激相关的神经胶质细胞毒性。此外，结合免疫球蛋白蛋白（Bip）、CCAAT/增强子结合蛋白同源蛋白（CHOP）、半胱天冬酶-12、磷酸化真核翻译起始因子2α（p-eIF2α）和剪接的X盒结合蛋白-1（XBP-1）mRNA的表达也增加。褪黑素以浓度依赖性方式降低ER应激反应基因和蛋白质的表达，从而减轻METH毒性诱导的ER应激。此外，褪黑素以浓度依赖性方式促进Bip伴侣蛋白的表达。综上所述，我们的研究结果表明，褪黑素可以保护神经胶质细胞免受METH诱导的ER应激所致的细胞死亡。
