Effects of the anticonvulsant drug valproic acid and related substances on the early development of the zebrafish ( Brachydanio rerio)

Abstract

The early development of the zebrafish Brachydanio rerio is being investigated as a possible test system for prescreening drugs suspected to be hazardous to humans. Experiments have been carried out to evaluate the teratogenic effect of the human antiepileptic drug valproic acid (VPA) and several chemically related substances. The experiments show the highly synchronous development of zebrafish embryos, even of batches laid by different parents. Effects due to drug treatment can be easily and accurately determined. VPA causes retardation and cessation of development. It generates malformations such as oedema, brain deformities, a shortened and bent tail, and bipartite axiation of the posterior trunk. The effects of the various substances tested were estimated and compared by measuring retardation of development. The related substances display similar effects, but differ in their effectiveness as they do in other test systems: 2-en-valproic acid and 4-en-valproic acid display weaker effects than VPA and propylhexanoic acid. Valpromide, methylhexanoic acid, pentenoic acid and diethylacetic acid display a weak effect or no effect at all. The effects in zebrafish appear to be more similar to those observed in hydroids and in mammalian whole embryo culture systems than to the effects in mammals in vivo. Differences may be best explained by differences in uptake and degradation of the drugs, and by the influence of the maternal organism in mammals.