Administration of the antiepileptic drug 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. Recent experiments demonstrate that 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 as a potential animal model. Relatively high doses and concentrations of VPA are needed in the mouse to produce neural tube defects, the human appears to be more sensitive in this regard. Maximal concentrations and not AUC (area under the concentration-time curve) values correlate with the incidence of neural tube defects in the mouse which could in part be explained by saturation of plasma protein binding, increased free drug available for placental transfer and the embryonic neuroepithelium acting as a "deep compartment". 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, branching on carbon atom 2 with two chains containing 3 carbon atoms each for maximum activity. If these two carbon chains are different, then enantiomers are present such as the R- and S-enantiomers of 2-n-propyl-4-pentenoic acid (4-en-VPA), 2-n-propyl-4-pentynoic acid (4-yn-VPA) and 2-ethylhexanoic acid. These enantiomers were synthesized and shown to be significantly different in regard to teratogenic potency. Pharmacokinetic studies indicate that both enantiomers of each compound reach the embryo to the same degree. Therefore, the intrinsic teratogenic activity of the enantiomers differ, suggesting a stereoselective interaction between the drugs and a chiral structure within the embryo, is involved in the mechanism of action. In sharp contrast to the teratogenic effect, the anticonvulsant activity and neurotoxicity of this compound class show broad structural specificity, opening the possibility for development of novel antiepileptic agents with low teratogenic potency such as 2-n-propyl-2-pentenoic acid (2-en-VPA). The molecular mechanism of the teratogenicity of VPA is quite unknown; of the several hypothesis suggested, the interaction of VPA with embryonic folate metabolism is discussed here.
Prenatal exposure to the antiepileptic drug valproic acid (VPA) has been associated with the formation of spina bifida aperta, meningocele, and meningomyelocele in the human. Until now, a direct relationship between VPA application and spina bifida has not been experimentally demonstrated. VPA was known only to induce exencephaly in mice, a defect of the anterior neural tube. Maximal sensitivity toward production of this defect was on day 8 of gestation (plug day = day 0). The closure of the posterior neuropore occurs later in the development of mice than the closure of the anterior neuropore. To investigate whether there is a direct relationship between VPA application during pregnancy and induction of spina bifida in mice, we administered various doses of the drug on day 9 of gestation, at three time intervals (at 0, 6, and 12 hr). This administration of VPA produced spina bifida aperta and spina bifida occulta in mice. High doses of VPA (3 x 450 and 3 x 500 mg/kg) induced a low rate of spina bifida aperta in the lumbosacral region. High incidences of spina bifida occulta, a less serious form of spina bifida, were induced with lower doses. This malformation was demonstrated in double-stained fetal skeletons by measurements of the distance between the cartilaginous ends of each vertebral arch. The occurrence of this defect and its localization was dose-dependent. The lumbar region was affected by all doses investigated (3 x 300, 3 x 350, 3 x 400, 3 x 450, and 3 x 500 mg/kg). The sacral/coccygeal region was affected additionally, but with higher doses (3 x 400, 3 x 450, and 3 x 500 mg/kg). A comparison of the results obtained with day 16 and 17 control fetuses showed that the pattern of gaps present in the lumbar and sacral region of the spinal cord in treated groups was drug-specific and not related to a developmental delay. Our results indicate that multiple administrations of VPA on day 9 of gestation in mice result in a low incidence of spina bifida aperta and a high incidence of spina bifida occulta, and provides a relevant model for the study of human spina bifida defects.
The antiepileptic drug valproic acid (VPA) is an established human teratogen causing spin bifida aperta. We recently developed a mouse model in which spina bifida aperta and occulta are induced with VPA. In a search for protection against neural tube defects, we investigated the effect of methionine on the incidence of VPA-induced spina bifida in the mouse. To induce spina bifida, we injected VPA (350 mg VPA-Na/kg body weight) subcutaneously three times on d 9 of gestation at 0, 6 and 12 h. In some mice, L-methionine (3 x 70 mg/kg body weight) was injected intraperitoneally 30 min before each VPA administration. When fetuses were examined on d 18, methionine treatment slightly reduced the VPA-induced spina bifida aperta rate from 5 to 1% (P > 0.05, no significant difference). The incidence of VPA-induced spina bifida occulta (90%) was significantly lower (28%) when methionine was also administered (P < 0.05). Examination on d 10 showed that the number of embryos in the mice administered VPA and methionine having an open neuroporus posterior was significantly lower than in mice administered VPA alone (P < 0.05). Pharmacokinetic studies indicated that VPA concentrations in maternal plasma and embryo did not differ between the two groups. Methionine reduces VPA-induced spina bifida in mice without altering VPA kinetics.
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