Effects of MK-801 on glutamate-induced swelling of astrocytes in primary cell culture.

The effects of glutamate and its agonists and antagonists on the swelling of primary astrocytes were studied. Glutamate (Glu), aspartate (Asp), homocysteate (HCA), and quisqualate (Quis) at 1 mM concentration caused a significant increase in astrocytic swelling as measured by the 3-0-methyl-[14C]-glucose, whereas kainate (KA), N-methyl-D-aspartate (NMDA), and receptor antagonists 2-amino-5-phosphonovaleric acid (APV), 2-amino-7-phosphonohepatanoic acid (APH), and kynurenic acid (Kynu) were not effective. This glial swelling was time-dependent since 1-hr or greater incubations with Glu or its agonists were needed to produce such an effect. Preincubation of glutamate or NMDA receptor anatogonists including Kynu, APH, and APV failed to ameliorate the Glu effects. However, MK-801, a noncompetitive NMDA antagonist, when added to the Glu-incubated astrocytes significantly reduced Glu-induced astrocytic swelling. MK-801 was also effective in reducing the astrocytic swelling induced by agonists including Asp, Quis, and HCA, suggesting that those agonists may share similar mechanisms of Glu in inducing astrocytic swelling. Since the cultured astrocytes lack the NMDA receptors, our data suggest that the observed beneficial effects of MK-801 on excitotoxin-induced swelling of astrocytes may be mediated by mechanisms other than NMDA receptors.