Ethanol promotes apoptosis in cerebellar granule cells by inhibiting the trophic effect of NMDA.
When primary cultures of cerebellar granule neurons are grown in a physiological concentration of KCl (5 mM) they undergo apoptosis, which can be prevented by growing the cells in the presence of N-methyl-D-aspartate (NMDA). We now show that ethanol inhibits this trophic effect of NMDA, i.e., promotes apoptosis, and also inhibits the NMDA-induced increase in intracellular Ca2+ concentration in cells grown in 5 mM KCl. Both effects of ethanol show a similar concentration dependence and are reversed by a high concentration of glycine, the co-agonist at the NMDA receptor. The data suggest that the effect of ethanol on apoptosis is mediated, at least in part, by inhibition of NMDA receptor function. This effect of ethanol to increase apoptosis could contribute to the previously described in vivo sensitivity of the developing cerebellum to ethanol-induced damage.
Bhave
S V
SV
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
Hoffman
P L
PL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002531:Cerebellum / Q000166:cytology; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005456:Fluorescent Dyes; D016257:Fura-2; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors
D002492:Central Nervous System Depressants; D018690:Excitatory Amino Acid Agonists; D005456:Fluorescent Dyes; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D016202:N-Methylaspartate; D011189:Potassium Chloride; D002118:Calcium; D016257:Fura-2