ANTICONVULSANT DRUG TOXICITY IN RAT-BRAIN CELL AGGREGATE CULTURES

As an extension of a previous validation study, the concentration-depe ndent effects of a series of anticonvulsant drugs were examined in agg regating cell cultures of foetal rat telencephalon. Cultures were trea ted either at an early (day 5 to day 14) or at an advanced (day 20 to day 28) developmental stage, and assayed for changes in the activities of the cell type-specific enzymes choline acetyltransferase (ChAT), a cetylcholinesterase (AChE), glutamic acid decarboxylase (GAD), glutami ne synthetase (GS) and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CN P). Five drugs (carbamazepine, diazepam, phenobarbital, phenytoin and valproate), currently used in the treatment of epileptic patients, wer e tested together with losigamone, a recently developed anticonvulsant . The results show distinct, concentration-dependent patterns of bioch emical changes for the different drugs, Phenytoin, carbamazepine, losi gamone and diazepam greatly reduced GAD, ChAT and AChE activities, ind icating a relatively high neuron-specific toxic potential. Diazepam pr oduced a more general pattern of toxicity and, in contrast to the anti convulsants, showed higher toxicity in less-differentiated cultures. P henobarbital and valproate slightly but significantly increased the ac tivities of several enzymes. The patterns of concentration-dependent e ffects observed in this three-dimensional cell culture system are in g ood agreement with the presumed neurotoxic and/or teratogenic potentia l of these drugs.