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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 \u03b3\u2010aminobutyric acid (GABA) and has anti\u2010oxidative and pro\u2010angiogenic features. However, its effects against Valproic acid\u2010evoked 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\u2010induced placental toxicity and abnormal fetal development in rats. After administration of Valproic acid (500\u2009mg\/kg\/day, orally) and\/or piracetam (500\u2009mg\/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\u2010uterine 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\u2010\u03b2 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\u2010\u03b2 axis alongside inhibition of oxidative stress by Piracetam can ameliorate Valproic acid\u2010evoked placental toxicity and, subsequently, fetal malformations in rats.<\/jats:p>","DOI":"10.1002\/jbt.70266","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T08:21:46Z","timestamp":1744618906000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Modulation of VEGF\/eNOS\/TGF\u2010\u03b2 Axis by Piracetam as a New Avenue to Ameliorate Valproic Acid\u2010Induced Placental Toxicity and Teratogenicity in Rats"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1835-5806","authenticated-orcid":false,"given":"Alzahraa A.","family":"Elhemiely","sequence":"first","affiliation":[{"name":"Department of Pharmacology Egyptian Drug Authority, EDA, Formerly NODCAR Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6734-5818","authenticated-orcid":false,"given":"Wessam H.","family":"Elesawy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences and Drug Manufacturing Misr University for Science and Technology 6th of October City Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27010104"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30107-8"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00246-4"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(00)01457-9"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16536"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2021.07.299"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semperi.2008.02.006"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.acthis.2007.02.008"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/1746-1596-5-24"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2011.06.025"},{"key":"e_1_2_12_12_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2015\/814543","article-title":"Angiogenesis in the Placenta: The Role of Reactive Oxygen Species Signaling","volume":"2015","author":"Pereira R. 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