ABSTRACT Background: Prenatal exposure to antiseizure medications (ASMs) poses a significant clinical dilemma, balancing maternal seizure control against the risk of fetal teratogenicity. Oxcarbazepine (OXC), a second-generation ASM, has been associated with hippocampal damage, yet the molecular mechanisms remain understudied. This study evaluates the neuroprotective efficacy of melatonin (MEL) against OXC-induced fetal neurotoxicity. Methods: Pregnant Wistar rats were randomized into four groups: Vehicle, MEL (10 mg/kg i.p.), OXC (100 mg/kg intragastric), and OXC+MEL, administered from gestational day (GD) 7-15. Fetal brains were harvested on GD19. Methodologies included histological morphometry (H&E, cresyl violet), apoptosis detection (TUNEL), oxidative stress profiling, and transcriptional analysis of the Nrf2 pathway and specific microRNAs. Results: OXC exposure induced severe hippocampal hypocellularity, elevated apoptotic indices, and significant oxidative stress (p < 0.05). Molecular analysis revealed a suppression of the Nrf2/HMOX1/NQO1 antioxidant pathway and dysregulation of miR-134-5p and miR-200a. Co-administration of MEL effectively reversed these pathological alterations, normalizing neuronal density, reducing apoptosis, normalizing oxidative markers and restoring homeostatic gene expression (p < 0.05). MEL alone had no adverse effects. Conclusion: MEL exerts potent neuroprotection against OXC-induced fetal hippocampal apoptosis by mitigating oxidative stress via Nrf2 pathway activation and normalizing key neurodevelopmental miRNAs, suggesting its potential as a safe adjunctive therapy in high-risk pregnancies.
