Brain malformations, oxidative and nitrosative stress induced prenatally by VPA in ICR mouse fetuses are counteracted by concomitant administration of S-adenosyl methionine.

Valproic acid (VPA) is a well - known teratogen and neuro-teratogen affecting many animals including humans. In rodents, prenatal VPA may induce a wide range of malformations and/or neurodevelopmental disorders depending on the time of administration and dose. We previously found that early postnatal administration of VPA in mice induced autistic like behaviour, and in the brain changes in gene expression and increased oxidative stress. S-adenosylmethionine (SAMe) normalized these deviations. We now assessed the possible alleviation by SAMe of the injuries caused by VPA administration during days 8.5, 9.5 of gestation on brain oxidative and nitrosative stress. ICR mice received intraperitoneally 300 mg/Kg VPA with or without 30 mg/kg SAMe, or a mixture of VPA and SAMe in the same ration. Fetuses were studied on Embryonic day 15.5. VPA induced fetal growth retardation, 32.5% of exencephaly, high resorption rate and, in the brain, increased Malondialdehyde (MDA) concentrations, increased antioxidant enzyme activity and elevated expression of antioxidant genes with increased expression of NOS1 and NOS2 genes, implying increased nitrosative stress. SAMe alone did not cause changes in the parameters tested. The addition of SAMe to VPA, abolished the VPA-induced damage. Administration of the mixture of VPA and SAMe did not induce any embryonic damage or changes in the redox potential of the brain, except for an unexplained up regulation of SOD1 and SOD2 genes. It is concluded that SAMe, an epigenetic modulator, neutralizes VPA's neuro-teratogenic effects when administered together with VPA during neurulation, like its postnatal effects.