The consequences of methylmercury exposure on interactive functions between astrocytes and neurons
The consequences of methylmercury exposure on interactive functions between astrocytes and neurons
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DOI：
10.1016/s0161-813x(01)00076-6
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发表时间：
2002-12-01
期刊：
影响因子：
3.4
通讯作者：
Aschner, M
中科院分区：
文献类型：
--
作者：
Allen, JW;Shanker, G;Aschner, M
甲基汞（MeHg）是一种高度神经毒性的环境中普遍存在的化学物质，其毒性作用的机制在很大程度上是未知的。维持细胞内谷胱甘肽（GSH）的最佳浓度对细胞防御自由基的损害至关重要。由于星形胶质细胞在向神经元提供谷胱甘肽前体方面起着至关重要的作用，因此研究的重点是甲基汞对两种细胞类型中胱氨酸运输的影响。星形胶质细胞通过三种独立的转运体积累胱氨酸，即系统X-AG-、系统X-C-和γ -谷氨酰转肽酶（GGT）。相比之下，神经元仅通过系统X-C-和GGT MeHg积累胱氨酸，可有效抑制星形胶质细胞（而不是神经元）对胱氨酸的摄取，这种作用可以通过抑制系统XAG-转运蛋白来完全解释。星形胶质细胞中谷氨酸的转运也被活性氧（ROS）抑制。因此，进一步的研究检验了巯基还原剂或氧化剂抑制h -3- d -天冬氨酸（谷氨酸类似物）星形细胞运输的能力。抗氧化过氧化氢酶显著减弱甲基汞诱导的星形细胞h -3-天冬氨酸摄取抑制。综上所述，这些研究表明，抑制胱氨酸摄取和星形胶质细胞GSH水平和外排的降低降低了神经元中合成GSH的前体的可用性。此外，mehg诱导H2O2的产生对星形细胞谷氨酸转运有抑制作用。这些影响可能会增加神经元对甲基汞诱导的氧化应激的易感性，以及过量的n -甲基d -天冬氨酸（NMDA）受体激活导致神经元死亡。(C) 2002爱思唯尔科学有限公司版权所有。
Methylmercury (MeHg) is a highly neurotoxic, environmentally ubiquitous chemical that exerts its toxic effects by largely unknown mechanisms. Maintenance of optimal intracellular concentrations of glutathione (GSH) is vital for cellular defenses against damage from free radicals. Since astrocytes play an essential role in providing GSH precursors to neurons, studies were directed at the effect of MeHg on cystine transport in both cell types. Astrocytes accumulated cystine via three independent transporters, referred to as system X-AG-, system X-C-, and gamma-glutamyltranspeptidase (GGT). In contrast, neurons accumulated cystine exclusively via system X-C- and GGT MeHg potently inhibited cystine uptake in astrocytes (but not in neurons), and this effect could be fully accounted for by inhibition of the system XAG- transporter The transport of glutamate in astrocytes is also inhibited by reactive oxygen species (ROS). Accordingly, additional studies examined the ability of thiol reducing or oxidizing agents to inhibit the astrocytic transport of H-3-D-aspartate, a glutamate analog. The antioxidant catalase significantly attenuated MeHg-induced inhibition of astrocytic H-3-aspartate uptake. Combinedly, these studies suggest that inhibition of cystine uptake and decreased astrocytic GSH levels and efflux reduce the availability of precursors for GSH synthesis in neurons. In addition, MeHg-induced generation of H2O2 plays a role in the inhibition of astrocytic glutamate transport. These effects likely increase neuronal vulnerability to MeHg-induced oxidative stress, and excess N-methyl D-aspartate (NMDA) receptor activation leading to neuronal demise. (C) 2002 Elsevier Science Inc. All rights reserved.