Dexamethasone induces cell death which may be blocked by NMDA receptor antagonists but is insensitive to Mg2+ in cerebellar granule neurons.
Since dexamethasone may elevate the Ca2+ influx through NMDA receptors, we have investigated mechanisms of dexamethasone toxicity in rat cerebellar granule neurons. Dexamethasone concentrations over 0.1 microM induced cell death that reached about 20% of the death induced by glutamate. Dexamethasone-induced cell death was reduced by more than 80% by the mineralocorticoid antagonist RU 28318 or the NMDA receptor antagonists MK 801 and CGP 39551, whereas RU 28318 rescued only approximately 30% of cells treated with glutamate, indicating that dexamethasone requires NMDA receptors to induce acute neuronal toxicity and that a fraction of the neurons showed this toxicity. Mg2+ reduced the cell death induced by glutamate at potassium concentrations of 1 mM and 5 mM, but not at 25 mM. In contrast, cell death induced by dexamethasone was not significantly reduced by Mg2+ in any of the potassium concentrations. Both glutamate and dexamethasone induced toxicity with translocation of the apoptosis inducer NGFI-B to the mitochondria seen after 30 min-2 h concomitant with activation of apoptosis inducing factor (AIF) and caspase-3. In conclusion, dexamethasone induces a rapid toxicity which is blocked by NMDA receptor antagonists other than Mg2+, and involves mitochondrial apoptosis inducer NGFI-B.
Jacobs
Chris M
CM
Department of Pharmaceutical Biosciences, Ullevål University Hospital, University of Oslo, P.O. Box 1068 Blindern, N-0316 Oslo, Norway.
Trinh
Minh D
MD
Rootwelt
Terje
T
Lømo
Jon
J
Paulsen
Ragnhild E
RE
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D020932:Nerve Growth Factor / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D000451:Mineralocorticoid Receptor Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D013148:Spironolactone; C041006:RU 28318; D003907:Dexamethasone; D020932:Nerve Growth Factor; D008274:Magnesium