Apoptotic cell death and caspase-3 activation induced by N-methyl-D-aspartate receptor antagonists and their prevention by insulin-like growth factor I.
The effect of N-methyl-D-aspartate (NMDA) receptor antagonists on cell viability was studied in rat primary cortical cells. NMDA antagonists [MK-801 and 2-amino-5-phosphonovalerate (APV)] induced cell shrinkage, nuclear condensation or fragmentation, and internucleosomal DNA fragmentation. Treatment of cells with MK-801 (an NMDA antagonist) for 1-2 days induced apoptotic cell death in a dose-dependent manner (1 nM to 10 microM). NMDA (25 microM), however, inhibited the MK-801 (0.1 microM)-induced apoptotic cell death. MK-801 and APV decreased the concentration of intracellular calcium ion. Activation of caspase-3 was accompanied by MK-801-induced cell death in a dose-dependent manner, and an inhibitor of caspase-3 reduced the cell death. Further, cycloheximide (0.2 microg/ml) completely protected the cells from MK-801-induced apoptotic cell death and caspase-3 activation. Insulin-like growth factor I completely attenuated MK-801-induced apoptotic cell death and caspase-3 activation. These results demonstrated that the moderate NMDA receptor activation is probably involved in the survival signal of the neuron.
Takadera
T
T
Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Matsuda
I
I
Ohyashiki
T
T
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003513:Cycloheximide / Q000494:pharmacology; D053938:DNA Fragmentation; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000032:analysis; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D011500:Protein Synthesis Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007334:Insulin-Like Growth Factor I; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D003513:Cycloheximide; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium