Hartnett K A, Stout A K, Rajdev S, Rosenberg P A, Reynolds I J, Aizenman E
Department of Neurobiology, University of Pittsburgh School of Medicine, Pennsylvania, U.S.A.
J Neurochem. 1997 May;68(5):1836-45. doi: 10.1046/j.1471-4159.1997.68051836.x.
Accumulation of intracellular Ca2+ is known to be critically important for the expression of NMDA receptor-mediated glutamate neurotoxicity. We have observed, however, that glutamate can also increase the neuronal intracellular Mg2+ concentration on activation of NMDA receptors. Here, we used conditions that elevate intracellular Mg2+ content independently of Ca2+ to investigate the potential role of Mg2+ in excitotoxicity in rat cortical neurons in vitro. In Ca2+-free solutions in which the Na+ was replaced by N-methyl-D-glucamine or Tris (but not choline), which also contained 9 mM Mg2+, exposure to 100 microM glutamate or 200 microM NMDA for 20 min produced delayed neuronal cell death. Neurotoxicity was correlated to the extracellular Mg2+ concentration and could be blocked by addition of NMDA receptor antagonists during, but not immediately following, agonist exposure. Finally, we observed that rat cortical neurons grown under different serum conditions develop an altered sensitivity to Mg2+-dependent NMDA receptor-mediated toxicity. Thus, the increase in intracellular Mg2+ concentration following NMDA receptor stimulation may be an underestimated component critical for the expression of certain forms of excitotoxic injury.
细胞内Ca2+的蓄积对于NMDA受体介导的谷氨酸神经毒性的表达至关重要。然而，我们观察到，谷氨酸在激活NMDA受体时也能增加神经元细胞内Mg2+的浓度。在此，我们采用独立于Ca2+升高细胞内Mg2+含量的条件，来研究Mg2+在体外大鼠皮质神经元兴奋毒性中的潜在作用。在无Ca2+的溶液中，用N-甲基-D-葡糖胺或Tris（而非胆碱）替代Na+，溶液中还含有9 mM Mg2+，暴露于100 μM谷氨酸或200 μM NMDA 20分钟会导致神经元延迟性死亡。神经毒性与细胞外Mg2+浓度相关，并且在激动剂暴露期间（而非暴露后立即）添加NMDA受体拮抗剂可阻断神经毒性。最后，我们观察到在不同血清条件下培养的大鼠皮质神经元对Mg2+依赖的NMDA受体介导的毒性产生了改变的敏感性。因此，NMDA受体刺激后细胞内Mg2+浓度的增加可能是某些形式兴奋毒性损伤表达中一个被低估的关键因素。
