# Dual Effect of Melatonin in Fetal Brain: Structural and Cellular Implications in a Rabbit Model of Intrauterine Growth Restriction

## TL;DR

Melatonin treatment in a rabbit model of IUGR shows both protective and harmful effects on fetal brain development.

## Contribution

The study reveals melatonin's dual effect on fetal brain development in IUGR, offering new insights into its neuroprotective and potentially harmful roles.

## Key findings

- Melatonin treatment increased oligodendrocyte numbers in IUGR fetuses.
- Melatonin showed detrimental effects in control groups, suggesting context-dependent actions.
- IUGR fetuses had lower body weights and survival rates compared to controls.

## Abstract

Intrauterine growth restriction (IUGR) is a condition in which the fetus fails to reach its genetic growth potential, often resulting in neurodevelopmental alterations. This study investigates the neuroprotective potential of gestational melatonin (MEL) treatment using an IUGR rabbit model. IUGR was induced by ligating the uteroplacental vessels of one uterine horn in pregnant rabbits, using the other horn as the control (CNT). Dams received either placebo (PLA) or MEL from gestational day 25 to 30, when pups were delivered by cesarean section. We performed a functional evaluation, followed by placental histopathology, oligodendrocyte quantification, neuronal arborization, and DAB (3, 3'-diaminobenzidine) staining of MEL receptors in the brain. IUGR groups exhibited significantly lower body weights and survival rates than CNTs, confirming successful model induction. Placental analysis indicated higher phase 2 ischemia in IUGR than CNTs, and reduced calcifications in MEL-treated groups. Brain analysis showed fewer oligodendrocytes and MEL receptors in PLA-treated IUGR groups compared to CNTs, partially reversed by MEL treatment. A dual response to MEL was observed in several endpoints, with beneficial effects on IUGR and detrimental effects on CNT groups. In conclusion, MEL demonstrates beneficial effects on the IUGR brain, particularly by increasing oligodendrocyte numbers, but its detrimental effects in CNT groups warrant caution in healthy pregnancies. These results indicate that substances can act as both therapeutic and toxic agents depending on physiological context, underscoring the need for further research to understand MEL’s mechanisms and optimize treatment strategies.

The online version contains supplementary material available at 10.1007/s12035-025-05032-y.