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 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.
Ehlers
K
K
Institute of Toxicology and Embryopharmacology, Free University Berlin, Germany.
Elmazar
M M
MM
Nau
H
H
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D015994:Incidence; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced / Q000453:epidemiology; D016135:Spinal Dysraphism / Q000139:chemically induced* / Q000453:epidemiology; D014635:Valproic Acid / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D014635:Valproic Acid; D008715:Methionine