Beta-carbolines induce apoptotic death of cerebellar granule neurones in culture.
Apart from its role in fast inhibitory transmission, only neurotrophic effects have been reported following activation of the GABAA receptor. Here, we show that n-butyl-beta-carboline-3-carboxylate and n-methyl-beta-carboline-3-carboxamide, which are negative allosteric modulators of the GABAA receptor acting at the benzodiazepine site, are neurotoxic for cerebellar granule neurones in culture. The beta-carboline-induced neuronal death is apoptotic since DNA internucleosomal fragmentation was induced and the neurotoxicity could be prevented by inhibitors of mRNA or protein synthesis. As GABA and benzodiazepine ligands (diazepam and Ro 15-1788) protect cerebellar granule cells against beta-carboline-induced toxicity, these data raise the possibility that the interaction between the beta-carbolines and the GABAA receptor is the triggering event leading to neuronal apoptosis.
Malgrange
B
B
Laboratory of Human Physiology and Pathophysiology, University of Liège, Belgium.
Rigo
J M
JM
Coucke
P
P
Belachew
S
S
Rogister
B
B
Moonen
G
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002243:Carbolines / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D007202:Indicators and Reagents; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism
D002243:Carbolines; D007202:Indicators and Reagents; D011963:Receptors, GABA-A