Valproic acid-induced placental toxicity: mechanistic insights and the therapeutic potential of bioactive folates

Valproic acid (VPA), an antiepileptic drug, has teratogenic effects. The study explores the protective potential of the bioactive folate derivatives 5-methyltetrahydrofolate (5-MTHF) and folinic acid against VPA-induced placental damage in a rat model. Pregnant Sprague-Dawley rats were divided into three groups: control, VPA-treated (1200 mg/kg, E10), and VPA combined with daily supplementation of bioactive folates. Histopathology demonstrated that VPA exposure resulted in marked thinning and disorganization of all placental layers, together with loss of decidual cells, depletion of glycogen cells in the junctional zone, and disrupted fetal vasculature in the labyrinth zone. These morphological abnormalities were associated with significant upregulation of pro-inflammatory cytokine markers TNF-α and IL-6 and an oxidative stress marker HO-1. In silico studies identified that VPA binds weakly to MTR (ΔG = - 4.5 kcal/mol), which may affect methylation processes. Bioactive folate supplementation preserved placental architecture, restored glycogen and decidual cell density, reduced vascular damage, and significantly attenuated inflammatory and oxidative markers. Such protection is most likely related to the metabolic readiness of 5-MTHF and folinic acid to bypass impaired pathways of folate metabolism. Our findings point to the superiority of bioactive folates over synthetic folic acid in counteracting VPA-induced placental toxicity. This study highlights the translational potential of the use of bioactive folate therapy in safeguarding placental health and fetal development in pregnancies requiring VPA therapy and its inclusion in clinical risk management strategies.

5-Methyltetrahydrofolate (5-MTHF); Bioactive folates; Epigenetic regulation; Folate metabolism; Folinic acid (Leucovorin); Inflammatory cytokines; Methionine synthase reductase (MTR); Neurodevelopmental protection; Oxidative stress; Placental toxicity; Pregnancy and antiepileptic drugs; Rat placenta model; Teratogenicity; VEGF/angiogenesis; Valproic acid.