Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning 110001, People's Republic of China.
Toxicology. 2012 Oct 28;300(3):112-20. doi: 10.1016/j.tox.2012.06.006. Epub 2012 Jun 18.
Methylmercury (MeHg) is one of the ubiquitous environmental toxicants, which can induce oxidative stress and an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. However, little is known of the interaction between oxidative stress and Glu metabolism play in MeHg poisoning rats. We have investigated the neuroprotective role of MK-801, a non-competitive N-methyl-d-aspartate receptors (NMDAR) antagonist, against MeHg-induced neurotoxicity. Fifty rats were randomly divided into five groups of 10 animals in each group: control group, MK-801 control group, MeHg-treated group (4 and 12 μmol/kg) and MK-801 pre-treated group. Administration of MeHg at a dose of 12 μmol/kg for four weeks significantly increased in ROS and total Hg levels and that caused lipid, protein and DNA peroxidative damage in cerebral cortex. In addition, MeHg also reduced nonenzymic (reduced glutathione, GSH) and enzymic (glutathione peroxidase, GPx and superoxide dismutase, SOD) antioxidants and enhanced neurocyte apoptosis rate in cerebral cortex. MeHg-induced ROS production appears to inhibit the activity of the glutamine synthetase (GS), leading to Glu metabolism dysfunction. Pretreatment with MK-801 at a dose of 0.3 μmol/kg prevented the alterations of the activities of PAG and GS and oxidative stress. In addition, pretreatment with MK-801 significantly alleviated the neurocyte apoptosis rate and histopathological damage. In conclusion, the results suggested ROS formation resulting from MeHg- and Glu-induced oxidative stress contributed to neuronal injury. MK-801 possesses the ability to attenuate MeHg-induced neurotoxicity in the cerebral cortex through mechanisms involving its NMDA receptor binding properties and antioxidation.
甲基汞（MeHg）是一种普遍存在的环境毒物，可诱导氧化应激和谷氨酸（Glu）代谢改变引起的间接兴奋毒性。然而，对于甲基汞中毒大鼠中氧化应激和 Glu 代谢之间的相互作用知之甚少。我们研究了 MK-801（一种非竞争性 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂）对 MeHg 诱导的神经毒性的神经保护作用。五十只大鼠随机分为五组，每组 10 只：对照组、MK-801 对照组、MeHg 处理组（4 和 12 μmol/kg）和 MK-801 预处理组。连续四周给予 MeHg 剂量为 12 μmol/kg 显著增加了 ROS 和总 Hg 水平，并导致皮质中脂质、蛋白质和 DNA 过氧化损伤。此外，MeHg 还降低了非酶（还原型谷胱甘肽，GSH）和酶（谷胱甘肽过氧化物酶，GPx 和超氧化物歧化酶，SOD）抗氧化剂，并增加了皮质中的神经细胞凋亡率。MeHg 诱导的 ROS 产生似乎抑制了谷氨酰胺合成酶（GS）的活性，导致 Glu 代谢功能障碍。以 0.3 μmol/kg 的剂量预先给予 MK-801 可防止 PAG 和 GS 以及氧化应激活性的改变。此外，MK-801 的预处理显著减轻了神经细胞凋亡率和组织病理学损伤。总之，这些结果表明，MeHg 和 Glu 诱导的氧化应激引起的 ROS 形成导致神经元损伤。MK-801 通过其 NMDA 受体结合特性和抗氧化作用，具有减轻皮质中 MeHg 诱导的神经毒性的能力。
