Abstract :
[en] Estetrol, a newly designated orphan drug, for attenuation of neonatal
Hypoxic-Ischemic Encephalopathy (HIE)
Ekaterine Tskitishvili1*, Christel Pequeux1, Renaud Viellevoye2, Michelle Nisolle3, Agnes Noël1 and Jean-Michel Foidart1
1Laboratory of Development Biology and Tumor, University of Liege, Liege, Belgium;
2Department of Pediatrics, University of Liege, Liege, Belgium;
3Department of Ob/Gyn, University of Liege, Liege, Belgium
Estetrol (E4) is a fetal estrogen synthesized only during human pregnancy. We aimed to study its role in attenuation of neonatal HIE. In vitro we defined antioxidative and cell viability effects of E4 on primary hippocampal cell cultures in oxidative stress condition by using lactate dehydrogenase (LDH) activity and cell survival (MTS) assays. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal HIE model of 7-day-old newborn rat pups was used. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for gray and white matter (MAP-2 and MBP), neurogenesis (DCX) and angiogenesis (VEGF) were evaluated by histo- and immunohistochemistry. The serum levels of brain damage markers (S100B and GFAP) were measured by ELISA. Our results demonstrate that E4 has significant antioxidative and cell survival properties along with neuroprotective and therapeutic effects. It decreases the early gray and white matter loss and promotes neuro- and angiogenesis in vivo. Combined use of E4 with other steroids does not have priority over the single use of E4. We also defined that E4's antioxidative actions mostly depend on ERα and ERβ, whereas neurogenesis and possibly promyelinating activities might be realized through ERβ. Treatment by E4 has no effects on body weight, brain weight or body temperature. E4 might become an important safe and physiological substance to treat neonatal HIE. Based on our data EMA granted orphan drug designation to E4.
References
1.Tskitishvili E, Nisolle M, Munaut C, Pequeux C, Gerard C, Noel A, Foidart JM.Estetrol attenuates Neonatal Hypoxic-Ischemic brain injury. Exp Neurol 2014; 261:298-307.
2. Tskitishvili E , Pequeux C, Munaut C, Viellevoye R, Nisolle M, Noel A, Foidart JM. Use of Estetrol with other Steroids for Attenuation of Neonatal Hypoxic-Ischemic brain injury: to combine or not to combine? Oncotarget 2016; 7(23):33722-43.
3. Tskitishvili E,Viellevoye R, Gerard C, Pequeux C, Munaut C, Nisolle M, Noel A, Foidart JM. Neonatal Hypoxic-Ischemic Encephalopathy: a new view of an old problem. Références en Gynécologie Obstetrique. 2016 17;1-4
4. Tskitishvili E, Pequeux C, Munaut C, Viellevoye R, Nisolle M, Noël A, Foidart JM. Estrogen receptors and estetrol-dependent neuroprotective actions: a pilot study. J Endocrinol. 2017; 232(1):85-95.
5.Foidart JM, Tskitishvili E. International patent application. Estrogenic components for use in the treatment of neurological disorders.
