Deng Yu, Xu Zhaofa, Xu Bin, Liu Wei, Wei Yangang, Li Yuehui, Feng Shu, Yang Tianyao
Department of Environmental Health, School of Public Health, China Medical University, North 2nd Road 92, Heping Ward, Shenyang, 110001, Liaoning, People's Republic of China,
Neurotox Res. 2014 Jul;26(1):40-51. doi: 10.1007/s12640-013-9448-6. Epub 2014 Feb 12.
Methylmercury (MeHg) is a ubiquitous environmental toxin that causes neurologic and developmental diseases. Oxidative damage and excitotoxicity are putative mechanisms, which underlie MeHg-induced neurotoxicity. In this study, the cross-talk between the oxidative damage and excitotoxicity pathways and the protective effects of riluzole in the rat cortex were explored. Rats were injected with MeHg and/or riluzole, and cold vapor atomic fluorescence spectrometry, hematoxylin and eosin staining, flow cytometry, fluorescence assays, spectrophotometry, real-time PCR, and Western blotting were used to evaluate neurotoxicity. The present study showed that (1) MeHg accumulated in the cerebral cortex and caused pathology. (2) MeHg caused oxidative damage by inducing glutathione (GSH) depletion, reactive oxygen species (ROS) production, inhibition of antioxidant enzyme activity, and alteration of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. (3) MeHg disrupted the glutamate transporters (GluTs), glutamate-glutamine cycle, and N-methyl-D-aspartate receptor expression and induced excitotoxicity. (4) Excitotoxicity resulted in disruption of GSH synthesis, calcium overloading, oxidative damage, and excessive ROS production. (5) Pretreatment with riluzole antagonized MeHg neurotoxicity by down regulating cross-talk between the oxidative damage and excitotoxicity pathways. In conclusion, the cross-talk between the oxidative damage and excitotoxicity pathways caused by MeHg exposure was linked by GluTs and calcium and inhibited by riluzole treatment.
甲基汞（MeHg）是一种普遍存在的环境毒素，可导致神经和发育疾病。氧化损伤和兴奋性毒性是推测的机制，是MeHg诱导神经毒性的基础。在本研究中，探讨了氧化损伤和兴奋性毒性途径之间的相互作用以及利鲁唑对大鼠皮质的保护作用。给大鼠注射MeHg和/或利鲁唑，并使用冷蒸气原子荧光光谱法、苏木精和伊红染色、流式细胞术、荧光测定法、分光光度法、实时PCR和蛋白质印迹法评估神经毒性。本研究表明：（1）MeHg在大脑皮质中蓄积并引起病理变化。（2）MeHg通过诱导谷胱甘肽（GSH）耗竭、活性氧（ROS）生成、抑制抗氧化酶活性以及改变核因子红细胞2相关因子2（Nrf2）信号传导来引起氧化损伤。（3）MeHg破坏谷氨酸转运体（GluTs）、谷氨酸-谷氨酰胺循环以及N-甲基-D-天冬氨酸受体表达并诱导兴奋性毒性。（4）兴奋性毒性导致GSH合成中断、钙超载、氧化损伤和过量ROS生成。（5）利鲁唑预处理通过下调氧化损伤和兴奋性毒性途径之间的相互作用来拮抗MeHg神经毒性。总之，MeHg暴露引起的氧化损伤和兴奋性毒性途径之间的相互作用通过GluTs和钙联系在一起，并被利鲁唑治疗所抑制。
