Dantrolene inhibits NMDA-induced 45Ca uptake in cultured cerebellar granule neurons.
Dantrolene is an inhibitor of a skeletal muscle subtype of ryanodine receptors that stabilizes intracellular calcium concentrations and exerts neuroprotective effects in neurons submitted to excitotoxic challenges. The mechanisms of dantrolene-induced neuroprotection are not clear. In this study, using a model of cultured rat cerebellar granule neurons, we demonstrated that dantrolene inhibits NMDA-evoked 45Ca uptake, indicating that this drug may inhibit the activity of NMDA receptor channels. Primary neuronal cultures were incubated for 10 min in Mg(2+)-free ionic medium with NMDA and 45Ca in the presence of different concentrations of dantrolene, then radioactivity in neurons was measured by liquid scintillation spectroscopy. The results demonstrated that dantrolene, applied at micromolar concentrations, inhibits NMDA-evoked 45Ca uptake in neurons in a dose-dependent manner. DMSO, a vehicle to dantrolene, in concentrations used in this study had no effect on NMDA-evoked 45Ca uptake. These results, indicating that dantrolene inhibits activation of the NMDA receptors, might at least partially explain the mechanisms of a dantrolene-evoked protection of neurons against excitotoxicity mediated by agonists of NMDA receptors.
Department of Neurochemistry, Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Street, 02-106 Warsaw, Poland.
Dorota
D
Makarewicz
Elzbieta
E
Ziemińska
Jerzy W
JW
Łazarewicz
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism* / Q000502:physiology; D003594:Cytoplasmic Granules / Q000378:metabolism* / Q000502:physiology; D003620:Dantrolene / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats
D016202:N-Methylaspartate; D003620:Dantrolene; D002118:Calcium