Valproic acid-induced neural tube defects.

Abstract

Antiepileptic drug therapy with valproic acid (VPA) during early pregnancy can result in a 1-2% incidence of spina bifida aperta, a closure defect of the posterior neural tube in the human. The predominant defect produced by VPA in the mouse is exencephaly, a closure defect of the anterior neural tube. An appropriate dosing regimen (consecutive doses of VPA on Day 9 of gestation) can also result in a low incidence of spina bifida aperta and a high incidence of spina bifida occulta in the mouse. It is likely that the parent drug and not a metabolite is the proximate teratogen. Structure-activity relationships show a strict structural requirement for high teratogenic potency: the molecule must contain an alpha-hydrogen atom, a carboxyl function and branching on C-2 with two chains containing three carbon atoms each for maximum activity. If these two carbon chains are different, then enantiomers are present. Pairs of enantiomers were synthesized and shown to be significantly different in regard to teratogenic potency. Both enantiomers of each compound reach the embryo to the same degree, therefore, the intrinsic teratogenic activity of the enantiomers differs. This suggests that stereoselective interaction occurs between the drugs and a chiral structure within the embryo. The molecular mechanism of the teratogenicity of VPA is not known; one hypothesis is that VPA interacts with embryonic folate metabolism.