In vitro effects of folate derivatives on valproate-induced neural tube defects in mouse and rat embryos

The anticonvulsant drug valproic acid (VPA), produces neural tube defects in mouse and rat embryos treated in vivo or in vitro. The mechanism for the drug's embryotoxic effect is unknown, but 5-formyltetrahydrofolate has been reported to decrease the incidence of VPA-induced neural tube defects in mice treated in vivo. In the present study we have examined the ability of 5-formyltetrahydrofolate, tetrahydrofolate, 5-methyltetrahydrofolate and folic acid to protect against VPA-induced neural tube defects in CD-1 mouse or CD rat embryos grown in a whole embryo culture system. Mouse embryos with 2-5 somite pairs were cultured for 48 hr beginning on gestation day 8; presomite stage rat embryos were cultured beginning on gestation day 9 (for both species gestation day 0 was taken as the day a vaginal sperm plug was found). VPA at 1.2 mm (rats) or 1.8 mm (mice) produced a high incidence of open neural tubes. None of the folate derivatives in concentrations up to 100 mug/ml was able to decrease the incidence of VPA-induced defects in either species. These data suggest that folate is not involved in the mechanism of VPA-induced neural tube defects.