Effect of Supplementation with Folinic Acid, Vitamin B6, and Vitamin B12 on Valproic Acid-Induced Teratogenesis in Mice

The effect of administration of folinic acid, vitamin B₆ + vitaminB₁₂, and their combination on valproic acid (VPA)-induced teratogenesiswas studied in NMRI mice. VPA (500 mg/kg, sc) was injected onDay 8 of gestation and the vitamins (two dose levels) were injectedip 1 hr before, immediately before, and 1 hr after VPA administration.Folinic acid significantly reduced VPA-induced resorptions (21–24%),and palate, rib, and sternebral malformations. Exencephaly andspina bifida occulta were also reduced (14 and 40%, respectively),but the difference was not statistically significant. On theother hand, vitamin B₆ + vitamin B₁₂ significantly reduced VPA-inducedexencephaly (23%), spina bifida occulta (80%), palate and ribmalformations, kidney abnormalities, and fetal weight retardation.A combination of the three vitamins was effective in reducingVPA-in duced exencephaly (23–30%), spina bifida occulta(60%), and palate and rib malformations. The protection againstVPA-induced malformations was not complete and was not alwaysdose related, and the reduction in exencephaly rate was onlysignificant in the absence of a reduction in resorption rate.Full-length cleft palate, sternebral malformations, and retardedsternebral and caudal ossification were, however, increasedby the high dose of combined vitamin administration. The presentstudy supports the view that VPA-induced teratogenesis may bemediated via an interaction with folate metabolism. Althoughfolinic acid and vitamin B₆ + vitamin B₁₂ can effectively reduceVPA malformations, the protection was not complete, which maysuggest the involvement of other factors. Furthermore, the doselevels should be carefully chosen since high doses of the combinedvitamins can actually increase the incidence of certain defects.