Estetrol Attenuates Neonatal Hypoxic-Ischemic Encephalopathy: Preclinical Studies

Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes of neonatal hypoxic-ischemic encephalopathy (HIE) accompanied by gray and white matter injuries occurring in neonates. Perinatal HIE still remains a challenge in perinatal medicine. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities. So far no medical treatment provides important neuroprotection against HIE. Studies of new neuroprotective agents in animal models of HIE may have importance for the development of new compounds and treatment strategies 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. It has important antioxidative activity. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal HIE model of 7-day-old newborn rat pups was used. 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 cell viability (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 brain damage markers (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Our results demonstrate for the first time that E4 has a significant neuroprotective and therapeutic effects. It 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. Taken together, E4 might become an important safe and physiological substance to treat neonatal HIE.