Tian Xing, An Li, Gao Ling-Yue, Bai Jun-Peng, Wang Jian, Meng Wei-Hong, Ren Tian-Shu, Zhao Qing-Chun
Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, China.
Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, China.
CNS Neurosci Ther. 2015 Jul;21(7):575-84. doi: 10.1111/cns.12408.
Compound MQA (1,5-O-dicaffeoyl-3-O-[4-malic acid methyl ester]-quinic acid) is a natural derivative of caffeoylquinic acid isolated from Arctium lappa L. roots. However, we know little about the effects of MQA on the central nervous system. This study aims to investigate the neuroprotective effects and underlying mechanisms of MQA against the neurotoxicity of N-methyl-d-aspartate (NMDA).
Pretreatment with MQA attenuated the loss of cell viability after SH-SY5Y cells treated with 1 mM NMDA for 30 min by MTT assay. Hoechst 33342 and Annexin V-PI double staining showed that MQA inhibited NMDA-induced apoptosis. In addition to preventing Ca(2+) influx, the potential mechanisms are associated with increases in the Bcl-2/Bax ratio, attenuation of cytochrome c release, caspase-3, caspase-9 activities, and expressions. Also, MQA inhibited NMDA-induced phosphorylation of ERK1/2, p38, and JNK1/2. Furthermore, deactivation of CREB, AKT, and GSK-3β, upregulation of GluN2B-containing NMDA receptors (NMDARs), and downregulation of GluN2A-containing NMDARs were significantly reversed by MQA treatment. Computational docking simulation indicates that MQA possesses a well affinity for NMDARs.
The protective effects of MQA against NMDA-induced cell injury may be mediated by blocking NMDARs. The potential mechanisms are related with mitochondrial apoptosis, ERK-CREB, AKT/GSK-3β, p38, and JNK1/2 pathway.
化合物MQA（1,5 - O - 二咖啡酰基 - 3 - O - [4 - 苹果酸甲酯] - 奎尼酸）是从牛蒡根中分离出的咖啡酰奎尼酸的天然衍生物。然而，我们对MQA对中枢神经系统的影响知之甚少。本研究旨在探讨MQA对N - 甲基 - D - 天冬氨酸（NMDA）神经毒性的神经保护作用及其潜在机制。
通过MTT法检测，用1 mM NMDA处理SH - SY5Y细胞30分钟后，MQA预处理可减轻细胞活力的丧失。Hoechst 33342和Annexin V - PI双重染色显示MQA抑制NMDA诱导的细胞凋亡。除了防止Ca(2+)内流外，潜在机制还与Bcl - 2/Bax比值增加、细胞色素c释放减少、caspase - 3、caspase - 9活性及表达降低有关。此外，MQA抑制NMDA诱导的ERK1/2、p38和JNK1/2磷酸化。此外，MQA处理可显著逆转CREB、AKT和GSK - 3β的失活，含GluN2B的N - 甲基 - D - 天冬氨酸受体（NMDARs）上调以及含GluN2A的NMDARs下调。计算对接模拟表明MQA对NMDARs具有良好的亲和力。
MQA对NMDA诱导的细胞损伤的保护作用可能是通过阻断NMDARs介导的。潜在机制与线粒体凋亡、ERK - CREB、AKT/GSK - 3β、p38和JNK1/2信号通路有关。
