METHIONINE REDUCES THE VALPROIC ACID-INDUCED SPINA-BIFIDA RATE IN MICE WITHOUT ALTERING VALPROIC ACID KINETICS

The antiepileptic drug valproic acid (VPA) is an established human ter atogen causing spina bifida aperta. We recently developed a mouse mode l 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 b ody 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 injec ted intraperitoneally 30 min before each VPA administration. When fetu ses were examined on d 18, methionine treatment slightly reduced the V PA-induced spina bifida aperta rate from 5 to 1% (P > 0.05, no signifi cant difference). The incidence of VPA-induced spina bifida occulta (9 0%) was significantly lower (28%) when methionine was also administere d (P < 0.05). Examination on d 10 showed that the number of embryos in the mice administered VPA and methionine having an open neuroporus po sterior 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. Met hionine reduces VPA-induced spina bifida in mice without altering VPA kinetics.