Albrecht J, Matyja E
Department of Neurotoxicology, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
Metab Brain Dis. 1996 Jun;11(2):175-84. doi: 10.1007/BF02069504.
Exposure to mercury vapor (Hg0) produces neurotoxic effects which are for the most part subsequent to its biotransformation in brain to the mercuric cation (Hg2 +), which has an exceptionally strong affinity towards the SH groups in proteins. However, neurologic symptoms are often encountered in subjects in which Hg+ concentration in the brain remains in the submicromolar range, markedly below the anticipated threshold for direct inhibition of cerebral metabolism and function. In this report we review biochemical and morphological evidence obtained in this and other laboratories in tissue culture studies suggesting that in such instances mercury neurotoxicity may be mediated by excitotoxic activity of glutamate (GLU). Mercuric chloride (MC) at 1 microM concentration (or less) inhibits GLU uptake and stimulates GLU release in cultured astrocytes, which in vivo is likely to result in excessive GLU accumulation in the extracellular space of the CNS. Inhibition of GLU uptake and stimulation of GLU release by MC may be attenuated by addition to the cultures of a cell membrane-penetrating agent dithiothreitol (DTT) but not of glutathione (GSH), which is not transported to the inside of the cells. However, MC-stimulated release of GLU is suppressed when the intracellular GSH levels are increased by metabolic manipulation. The results indicate that the MC-vulnerable SH groups critical for GLU transport are located within the astrocytic membranes. Ultrastructural evidence for GLU-mediated MC neurotoxicity came from studies in an organotypic culture of rat cerebellum. We have shown that: 1) 1 microM MC lowers the threshold of GLU neurotoxicity, 2) the combined neurotoxic effect of GLU plus MC is attenuated by DTT but not by GSH, which is consistent with the involvement of impaired astrocytic GLU transport, and 3) neuronal damage induced by GLU plus MC becomes less accentuated in a medium with dizocilpine (MK-801), a noncompetitive NMDA receptor antagonist.
接触汞蒸气（Hg0）会产生神经毒性作用，在很大程度上这是其在大脑中生物转化为汞离子（Hg2 +）之后的结果，汞离子对蛋白质中的SH基团具有极强的亲和力。然而，在大脑中Hg+浓度仍处于亚微摩尔范围内的受试者中，经常会出现神经症状，这明显低于直接抑制大脑代谢和功能的预期阈值。在本报告中，我们回顾了在本实验室和其他实验室的组织培养研究中获得的生化和形态学证据，这些证据表明在这种情况下，汞的神经毒性可能由谷氨酸（GLU）的兴奋毒性活性介导。1微摩尔浓度（或更低）的氯化汞（MC）会抑制培养的星形胶质细胞对GLU的摄取并刺激GLU释放，在体内这可能导致中枢神经系统细胞外空间中GLU过度积累。向培养物中添加细胞膜穿透剂二硫苏糖醇（DTT）可减弱MC对GLU摄取的抑制和对GLU释放的刺激，但添加不能转运到细胞内部的谷胱甘肽（GSH）则无效。然而，当通过代谢操作提高细胞内GSH水平时，MC刺激引起的GLU释放会受到抑制。结果表明，对GLU转运至关重要的易受MC影响的SH基团位于星形胶质细胞膜内。GLU介导的MC神经毒性的超微结构证据来自大鼠小脑器官型培养的研究。我们已经表明：1）1微摩尔MC降低了GLU神经毒性的阈值；2）GLU加MC的联合神经毒性作用可被DTT减弱，但不能被GSH减弱，这与星形胶质细胞GLU转运受损有关；3）在含有非竞争性NMDA受体拮抗剂地佐环平（MK-801）的培养基中，GLU加MC诱导的神经元损伤变得不那么严重。
