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Methionine Reduces the Valproic Acid-Induced Spina Bifida Rate in Mice without Altering Valproic Acid Kinetics^1,2,3,

Institute of Toxicology and Embryopharmacology, Free University Berlin, D-14195 Berlin, Germany ^* Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia

The antiepileptic drug valproic acid (VPA) is an established human teratogen causing spina 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.

KEY WORDS: • spina bifida • valproic acid • methionine • pharmacokinetics • mice

¹ Presented in poster form at the 22nd Teratology Society Conference, September, 1994, Prague, Czech Republic (Ehlers, K., Drews, E., Elmazar, M.M.A. & Nau, H. The amino acid methionine reduces the valproic acid-induced spina bifida rate in the mouse).

² Supported by grants from the European Community (Biotech Program) and American Biogenetic Sciences.

³ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

⁴ To whom correspondence and reprint requests should be addressed.

Manuscript received 24 January 1995. Revision accepted 11 September 1995.