Inhibition of nitric oxide synthesis enhances teratogenic effects induced by valproic Acid.

BACKGROUND/AIM The mechanism of valproic acid (VPA)-induced teratogenicity is poorly known. This study was carried out to probe into the potential consequences of nitric oxide (NO) deprivation on VPA teratogenicity. MATERIALS AND METHODS On gestation day 8, mice were injected with a non-teratogenic dose (20 mg/kg) of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl esther (L-NAME). Thirty minutes later, animals received a teratogenic dose of VPA (400 or 500 mg/kg). Developmental end-points were evaluated near the end of gestation. RESULTS After treatment with VPA at 400 mg/kg, 35.2% of fetuses exhibited skeletal teratogenesis. The rate of skeletally affected fetuses significantly increased to 53.7% after L-NAME co-administration. In the group treated with VPA at 500 mg/kg group, L-NAME pre-treatment increased the incidence of exencephaly from 5.4% to 22.2%. CONCLUSION Inhibition of NO synthesis can result in an enhancement of VPA-induced teratogenesis.