Modulation of VEGF/eNOS/TGF‐β Axis by Piracetam as a New Avenue to Ameliorate Valproic Acid‐Induced Placental Toxicity and Teratogenicity in Rats

ABSTRACT Valproic acid (VPA) is a very effective therapy used to treat generalized epilepsy, but it must be avoided during pregnancy as it leads to a high risk of teratogenesis. Its teratogenic effect is believed to be due to its placental toxic effect, altering angiogenesis and inducing oxidative stress. Piracetam (PIRA) is a derivative of the neurotransmitter γ‐aminobutyric acid (GABA) and has anti‐oxidative and pro‐angiogenic features. However, its effects against Valproic acid‐evoked placental toxicity and abnormal fetal development have not been mechanistically examined. Herein, the present study targets angiogenesis and oxidative stress by Piracetam to investigate the potential modulation of Valproic acid‐induced placental toxicity and abnormal fetal development in rats. After administration of Valproic acid (500 mg/kg/day, orally) and/or piracetam (500 mg/kg/day, orally) from the 6th to 15th of gestation, fetuses and placenta were obtained for analysis. The present findings revealed that Piracetam improved the histopathological lesions in the placenta and restored the labyrinth zone area percent. Moreover, it improved the intra‐uterine growth retardation (IUGR) via restoring fetal body weight and length and also ameliorated all external malformations (subcutaneous hemorrhage, fore limb, and hind limb anomalies) and additionally amended the skeletal lack of ossification. These favorable effects of Piracetam were mediated by the enhancement of placental angiogenesis via the VEGF/eNOS/TGF‐β pathway and attenuating placental oxidative stress, which appeared as decreased MDA content and increased GSH and TAC levels. In conclusion, activation of placental angiogenesis via the VEGF/eNOS/TGF‐β axis alongside inhibition of oxidative stress by Piracetam can ameliorate Valproic acid‐evoked placental toxicity and, subsequently, fetal malformations in rats.