Estetrols’ Potential for Neuroprotection Following the injury to the Developing Brain: Preclinical Studies

Context: Hypoxic-Ischemic encephalopathy (HIE) remains a major cause of perinatal brain injury. The brain rapidly increases in size, shape and complexity during the second and third trimesters. A sentinel event in late pregnancy or the intrapartum period may have an acute profound effect on a previously neurologically intact fetus, leading to the development of (HIE). The nature of the deficits is dependent on the gestational age and severity of the insult, though it is seldom reported in preterm infants. Studies in animal models of HIE may provide important information for the development of treatment for this pathological condition. Estetrol (E4) is a recently described estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver.
Objective: In this study, we evaluated E4’s neuroprotective and therapeutic potency in neonatal (in vivo) HIE model of the immature 7-day-old
newborn rat.
Methods: Rat pups body temperatures were examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for neuronal early grey matter damage (microtubule-associated protein-2 (MAP-2)), neurogenesis (doublecortin (DCX)) and angiogenesis (vascular-endothelial growth factor (VEGF)) were evaluated by histo- and immunohistochemistry. The serum levels of two markers of brain damage (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA.
Results: Our results demonstrate that E4 has a significant neuroprotective and therapeutic effects. Estetrol decreases the early gray matter loss, and promotes neuro- and angiogenesis in vivo. Estetrol treatment has no effects on body weight, brain weight or body temperature.
Conclusion: Taken together, E4 might become an important safe and physiological substance to treat neonatal HIE.