BETA-CARBOLINES INDUCE APOPTOTIC DEATH OF CEREBELLAR GRANULE NEURONS IN CULTURE

Apart from its role in fast inhibitory transmission, only neurotrophic effects have been reported following activation of the GABA(A) recept or. Here, we show that n-butyl-beta-carboline-3-carboxylate and n-meth yl-beta-carboline-3-carboxamide, which are negative allosteric modulat ors of the GABA(A) receptor acting at the benzodiazepine site, are neu rotoxic for cerebellar granule neurones in culture. The beta-carboline -induced neuronal death is apoptotic since DNA internucleosomal fragme ntation was induced and the neurotoxicity could be prevented by inhibi tors of mRNA or protein synthesis. As GABA and benzodiazepine ligands (diazepam and Ro 15-1788) protect cerebellar granule cells against bet a-carboline-induced toxicity, these data raise the possibility that th e interaction between the (b)eta-carbolines and the GABA(A) receptor i s the triggering event leading to neuronal apoptosis.