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IN VITRO SCREENING FOR ANTICONVULSANT TERATOGENESIS IN NEURAL PRIMARY CULTURES AND CELL LINES

Objective


The teratogenic potential of pharmaceutical agents was evaluated in vitro using an antiproliferative assay in clonal cell lines and a cytotoxicity assay employing primary cultures of cerebral cortex neurons at different stages of their development. Anticonvulsant agents with an ability to induce neural tube defects in vivo, valproate and the benzodiazepines (diazepam and clonazepam), were shown to have an antiproliferative action in neuroblastoma and glioma cell lines at 2-3 times their therapeutic serum concentrations and this was not due to cytotoxic action. Agents with a cytoxic action (phenytoin and some barbiturates) could be associated with their known in vivo impairment of neurodevelopment. Nonteratogenic analogues of valproate had no antiproliferative effect in clonal cell lines and the cytotoxic effect of certain barbiturates on primary cortical neurons had a specific structure activity requirement. In vivo systems evaluating induction of early differentiation markers and change in adhesiveness had poor discriminatory potential. The convulsive agent lindane was shown to inhibit picrotoxin binding and to facilitate transmitter release in vitro.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Address
Serrano 117
Madrid
Spain