Prevention of valproic acid-induced neural tube defects by sildenafil citrate

- Valproic acid-induced neural tube defects and axial skeletal malformations in mice.
- Sildenafil citrate is a type 5 phosphodiesterase inhibitor enhancing NO/cGMP-mediated effects.
- Pretreatment with sildenafil citrate decreased teratogenic effects of vaplroic acid.

This study was undertaken to test the effects of sildenafil citrate (SC), a type 5 phosphodiesterase inhibitor, on valproic acid (VPA)-induced teratogenesis. On gestation day (GD) 8, ICR (CD-1) mice were treated by gastric intubation with SC at 0 (vehicle), 1.0, 2.5, 5.0 or 10 mg/kg. One hour later, animals received a teratogenic dose of VPA (600 mg/kg) or vehicle. Developmental endpoints were evaluated near the end of gestation. Twenty-eighth percent of fetuses exposed to VPA had neural tube defects (exencephaly). Pretreatment with SC at 2.5, 5.0 or 10 mg/kg significantly reduced the rate of VPA-induced exencephaly to 15.9%, 13.7%, and 10.0%, respectively. Axial skeletal defects were observed in 75.8% of VPA-exposed fetuses. Pre-treatment with SC at 10 mg/kg, but not at lower doses, significantly decreased the rate of skeletally affected fetuses to 61.6%. These results show that SC, which prolongs nitric oxide (NO) signaling action protects from VPA-induced teratogenesis.