NMDA RECEPTOR-MEDIATED NEUROTOXICITY - A PARADOXICAL REQUIREMENT FOR EXTRACELLULAR MG2+ IN NA+ CA2+-FREE SOLUTIONS IN RAT CORTICAL-NEURONS IN-VITRO/

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 neuro nal intracellular Mg2+ concentration on activation of NMDA receptors. Here, we used conditions that elevate intracellular Mg2+ content indep endently of Ca2+ to investigate the potential role of Mg2+ in excitoto xicity in rat cortical neurons in vitro. In Ca2+-free solutions in whi ch the Na+ was replaced by N-methyl-D-glucamine or Tris (but not choli ne), which also contained 9 mM Mg2+, exposure to 100 mu M glutamate or 200 mu M NMDA for 20 min produced delayed neuronal cell death. Neurot oxicity was correlated to the extracellular Mg2+ concentration and cou ld be blocked by addition of NMDA receptor antagonists during, but not immediately following, agonist exposure, Finally, we observed that ra t cortical neurons grown under different serum conditions develop an a ltered 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 t he expression of certain forms of excitotoxic injury.