ANTI-EPILEPTIC DRUGS AND BRAIN AND BEHAVIOURAL DEVELOPMENT IN ANIMAL MODELS AND HUMANS

Abstract

Wediscussstudiesbasedonanimalmodelsaswellasthosethathavefollowed-upchildrenexposed to AEDs in-utero. Careful longitudinal human research can document thecognitiveandbehaviouraleffects,butthelongtimescalesrequiredandinabilitytoruleout confounding variables, both genetic and environmental, are serious limitations.Animal studies are based on the assumption that many developmental processes areconserved between the animals used in the models (most often rodents) and humans.However, the hugely expanded cortex and cognitive and behavioural repertoire ofhumans implies that there are aspects that can not be well modelled. In addition,due to differences in how susceptible different species are to various teratogens,studies always need to be done in man as well. Nevertheless, an understanding of themolecular mechanisms of neuro-teratogenesis derived from animal models will helpus predict which anti-epileptic drugs are likely to cause fewer neuro-developmentalproblems in humans.In the first section we present a simplified account of how the developmentof the human CNS is regulated by evolutionary conserved genetic and signallingpathways. We emphasize these pathways because AEDs can potentially interferewith them. Because of the complexity and duration of brain development there isa wealth of critical periods during which AEDs have the potential to interfere with