Methylmercury (MeHg) is a potent neurotoxin,which leads to a wide range of intracellular effects. The molecular mechanismsassociated to MeHg‐induced neurotoxicity have not been fully understood.Oxidative stress, as well as synaptic glutamate (Glu) dyshomeostasis have beenidentified as two critical mechanisms during MeHg‐mediated cytotoxicity. Here,we developed a rat model of MeHg poisoning to evaluate its neurotoxic effectsby focusing on cellular oxidative stress and synaptic Glu disruption. Inaddition, we investigated the neuroprotective role of alpha‐lipoic acid (α‐LA), a natural antioxidant, todeeply explore the underlying interaction between them. Fifty‐six rats wererandomly divided into four groups: saline control, MeHg treatment (4 or 12μmol/kg MeHg), and α‐LApre‐treatment (35 μmol/kg α‐LA+12μmol/kg MeHg). Rats exposed to 12 μmol/kg MeHg induced neuronal oxidativestress, with ROS accumulation and cellular antioxidant system impairment. Nrf2 andxCT pathways were activated with MeHg treatment. The enzymatic or non‐enzymaticof cellular GSH synthesis were also disrupted by MeHg. On the other hand, the abnormalactivities of GS and PAG disturbed the “Glu‐Gln cycle”, leading to NMDARsover‐activation, Ca2+ overload, and the calpain activation, which acceleratedNMDARs degradation. Meanwhile, the high expressions of phospho‐p44/42 MAPK,phospho‐p38 MAPK, phospho‐CREB, and the high levels of caspase 3 and Bax/Bcl‐2 finallyindicated the neuronal apoptosis after MeHg exposure. Pre‐treatment with α‐LA significantly preventedMeHg‐induced neurotoxicity. In conclusion, the oxidative stress and synapticGlu dyshomeostasis contributed to MeHg‐induced neuronal apoptosis. Alpha‐LAattenuated these toxic effects through mechanisms of anti‐oxidation andindirect Glu dyshomeostasis prevention

中文翻译：

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在甲基汞诱导的大鼠大脑皮层神经元凋亡过程中，氧化应激加速突触谷氨酸稳态失调和 NMDARs 紊乱

甲基汞 (MeHg) 是一种强效神经毒素，可导致广泛的细胞内效应。与甲基汞诱导的神经毒性相关的分子机制尚未完全清楚。氧化应激和突触谷氨酸 (Glu) 失调已被确定为甲基汞介导的细胞毒性过程中的两个关键机制。在这里，我们开发了一个 MeHg 中毒大鼠模型，通过关注细胞氧化应激和突触 Glu 破坏来评估其神经毒性作用。此外，我们研究了天然抗氧化剂 α-硫辛酸 (α-LA) 的神经保护作用，以深入探索它们之间的潜在相互作用。56只大鼠随机分为四组：生理盐水对照组、甲基汞处理（4或12μmol/kg甲基汞）和α-LA预处理（35μmol/kgα-LA+12μmol/kg甲基汞）。大鼠暴露于 12 μmol/kg MeHg 诱导神经元氧化应激，ROS 积累和细胞抗氧化系统受损。甲基汞处理激活了 Nrf2 和 xCT 通路。MeHg 也破坏了细胞 GSH 合成的酶促或非酶促合成。另一方面，GS和PAG的异常活动扰乱了“Glu-Gln循环”，导致NMDARs过度激活、Ca2+过载和钙蛋白酶激活，加速了NMDARs的降解。同时，磷酸-p44/42 MAPK、磷酸-p38 MAPK、磷酸-CREB的高表达以及半胱天冬酶3和Bax/Bcl-2的高水平最终表明甲基汞暴露后神经元凋亡。用 α-LA 预处理可显着防止甲基汞诱导的神经毒性。总之，氧化应激和突触Glu动态平衡有助于甲基汞诱导的神经元凋亡。