Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan, 250012, People's Republic of China.
Metab Brain Dis. 2019 Apr;34(2):545-555. doi: 10.1007/s11011-019-0382-z. Epub 2019 Feb 12.
Oxidative stress has been suggested to play an important role in neuronal injury. Ethyl gallate (EG) is the ethyl ester of gallic acid which has been acknowledged as an antioxidant. We previously demonstrated that EG effectively inhibited HO-induced cytotoxicity and decreased the ROS levels in PC12 cells, while the relevant mechanisms of action of this compound remain largely uncharacterized. The present study was carried out in an attempt to clarify the underlying mechanisms of EG against HO-induced neurotoxicity in PC12 cells. EG pretreatment attenuated HO-induced mitochondrial dysfunction as indicated by the decreased caspase-9/-3 activation, PARP cleavage, mitochondrial membrane potential (MMP) depletion, Bax/Bcl-2 ratio, cytochrome c release and ROS overproduction. Furthermore, EG treatment resulted in nuclear translocation of Nrf2 along with increased expression of ARE-dependent cytoprotective genes, such as γ-GCS and NQO1, which indicated EG as an Nrf2 pathway activator. Silencing of Nrf2 signaling by siRNA abrogated the protective effects offered by EG on HO-induced PC12 cells injury, which suggested the important role of Nrf2 pathway in the protection of EG against oxidative stress induced PC12 cell apoptosis. These results taken together indicated that EG protects PC12 cells against HO-induced cell mitochondrial dysfunction possibly through activation of Nrf2 pathway. EG might be a potential candidate for further preclinical study aimed at the prevention and treatment of neurodegenerative diseases.
氧化应激被认为在神经元损伤中发挥重要作用。没食子酸乙酯（EG）是没食子酸的乙酯，已被确认为一种抗氧化剂。我们之前的研究表明，EG 可有效抑制 HO 诱导的细胞毒性并降低 PC12 细胞中的 ROS 水平，而该化合物的相关作用机制仍在很大程度上尚未确定。本研究旨在阐明 EG 对 PC12 细胞中 HO 诱导的神经毒性的潜在作用机制。EG 预处理可减轻 HO 诱导的线粒体功能障碍，表现为 caspase-9/-3 激活、PARP 切割、线粒体膜电位（MMP）耗竭、Bax/Bcl-2 比值、细胞色素 c 释放和 ROS 过度产生减少。此外，EG 处理导致 Nrf2 核转位以及 ARE 依赖性细胞保护基因如 γ-GCS 和 NQO1 的表达增加，表明 EG 是 Nrf2 途径的激活剂。siRNA 沉默 Nrf2 信号通路可消除 EG 对 HO 诱导的 PC12 细胞损伤的保护作用，表明 Nrf2 途径在 EG 对抗氧化应激诱导的 PC12 细胞凋亡的保护作用中起重要作用。这些结果表明，EG 通过激活 Nrf2 途径保护 PC12 细胞免受 HO 诱导的细胞线粒体功能障碍。EG 可能是进一步进行预防和治疗神经退行性疾病的临床前研究的潜在候选药物。
