1. Neuroprotective effects of maternal melatonin administration in early-onset placental insufficiency and fetal growth restriction.
- Author
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Malhotra A, Rocha AKAA, Yawno T, Sutherland AE, Allison BJ, Nitsos I, Pham Y, Jenkin G, Castillo-Melendez M, and Miller SL
- Subjects
- Animals, Female, Pregnancy, Sheep, Disease Models, Animal, Myelin Sheath drug effects, Myelin Sheath metabolism, Microglia drug effects, Microglia metabolism, Melatonin administration & dosage, Melatonin pharmacology, Fetal Growth Retardation prevention & control, Fetal Growth Retardation drug therapy, Neuroprotective Agents administration & dosage, Placental Insufficiency drug therapy, Brain drug effects, Brain pathology
- Abstract
Background: Early-onset fetal growth restriction (FGR) is associated with adverse outcomes. We hypothesised that maternal melatonin administration will improve fetal brain structure in FGR., Methods: Surgery was performed on twin-bearing ewes at 88 days (0.6 gestation), and FGR induced in one twin via single umbilical artery ligation. Melatonin was administered intravenously (6 mg/day) to a group of ewes commencing on day of surgery until 127 days (0.85 gestation), when the ewe/fetuses were euthanized, and fetal brains collected., Results: Study groups were control (n = 5), FGR (n = 5), control+melatonin (control+MLT; n = 6) and FGR+melatonin (FGR + MLT; n = 6). Melatonin administration did not significantly alter fetal body or brain weights. Myelin (CNPase+) fibre density was reduced in FGR vs. control animals in most brain regions examined (p < 0.05) and melatonin treatment restored CNPase fibre density. Similar but less pronounced effect was seen with mature myelin (MBP+) staining. Significant differences in activated microglia (Iba-1) activity were seen between lamb groups (MLT mitigated FGR effect) in periventricular white matter, subventricular zone and external capsule (p < 0.05). Similar effects were seen in astrogliosis (GFAP) in intragyral white matter and cortex., Conclusions: Maternal melatonin administration in early onset FGR led to improved myelination of white matter brain regions, possibly mediated by decreased inflammation., Impact: Maternal melatonin administration might lead to neuroprotection in the growth-restricted fetus, possibly via dampening neuroinflammation and enhancing myelination. This preclinical study adds to the body of work on this topic, and informs clinical translation. Neuroprotection likely to improve long-term outcomes of this vulnerable infant group., (© 2024. The Author(s).)
- Published
- 2024
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