Estetrol and its effects on the damaged brain

Estetrol; Estrogen receptors; Neonatal hypoxic-ischemic encephalopathy; Neurogenesis; Cerebro-angiogenesis; Myelination; Hippocampus; Cortex; S100B; GFAP

Abstract :

[en] Estrogens play an important role not only in reproductive system but in the central nervous system as well. Major events of ontogenesis occur earlier in pregnancy are connected to the formation of estrogen receptors and expression of estrogens leading to the normal physiological development of the central nervous system, though development of brain by itself is a complex process and lasts during the whole pregnancy. Estetrol (E4) is a recently described natural estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. Its role in the central nerovus system is not fully understood. Our studies showed for the first time and proved impressive antioxidative effects of E4 in vitro and proved its tremendous neuroprotective, promyelinating, neurogenic and cerebro-angiogenic properties in vivo. E4 dicreases brain damage markers (S100B and GFAP) in blood assuming that E4 attenuates neonatal hypoxic-ischemic encephalopathy in vivo. We have also shown that the combined use of E4 with other steroids do not have any priority over the signle use of E4. E4’s antioxidative actions mostly depend on ERα and ERβ, whereas neurogenesis and possibly promyelinating activities might be realized through ERβ. Taken together our studies suggest importance of E4 treatment possibly not only in neonates but in adults with different neurological diseases like that that opening new directions for the use of E4 in clinical practice in neurological diseases.

Disciplines :

Neurology
Reproductive medicine (gynecology, andrology, obstetrics)
Pediatrics

Author, co-author :

Tskitishvili, Ekaterine ; Université de Liège - ULiège > Cancer-Tumours and development biology

Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques

Language :

English

Title :

Estetrol and its effects on the damaged brain

Alternative titles :

[en] Estetrol and the brain

Publication date :

May 2019

Main work title :

Sex Steroids' Effects on Brain, Heart and Vessels

Editor :

Diaz Brinton, Roberta

Genazzani, Andrea R.

Simoncini, Tomasso

Stevenson, Jhon C.

Publisher :

Springer publishing

ISBN/EAN :

978-3030113544

Collection name :

Frontiers in Gynecological Endocrinology, Volume 6

Peer reviewed :

Peer reviewed

Available on ORBi :

since 07 June 2019

Statistics

Number of views

103 (13 by ULiège)

Number of downloads

6 (4 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

Charles H. Rodeck, Martin J. Whittle, Fetal medicine: basic science and clinical practice. 2nd edition, 2009, Elsevier Health Sciences, London.
Shiota K. Prenatal development of the human central nervous system, normal and abnormal. Donald School J Ultrasound Obstet Gynecol. 2015;9(1):61–6.
Gonzalez M, Cabrera-Socorro A, Perez-Garcia CG, Fraser JD, Lopez FJ, Alonso R, et al. Distribution patterns of estrogen receptor alpha and beta in the human cortex and hippocampus during development and adulthood. J Comp Neurol. 2007;503(6):790–802. https://doi. org/10.1002/cne.21419.
Hart SA, Patton JD, Woolley CS. Quantitative analysis of ER alpha and GAD colocalization in the hippocampus of the adult female rat. J Comp Neurol. 2001;440:144–55. https://doi. org/10.1002/cne.1376.
Shughrue PJ, Merchenthaler I. Evidence for novel estrogen binding sites in the rat hippocampus. Neuroscience. 2000;99:605–12. https://doi.org/10.1210/endo.139.12.6525.
O’Keefe JA, Li Y, Burgess LH, Handa RJ. Estrogen receptor mRNA alterations in the developing rat hippocampus. Brain Res Mol Brain Res. 1995;30:115–24. https://doi. org/10.1016/0169-328X(94)00284-L.
Solum DT, Handa RJ. Localization of estrogen receptor alpha (ER-alpha) in pyramidal neurons of the developing rat hippocampus. Brain Res Dev Brain Res. 2001;28:165–75. https://doi. org/10.1016/S0165-3806(01)00171-7.
Nomura M, Korach KS, Pfaff DW, Ogawa S. Estrogen receptor b (ERb) protein levels in neurons depend on estrogen receptor a (ERa) gene expression and on its ligand in a brain region-specific manner. Mol Brain Res. 2003;110(2003):7–14. https://doi.org/10.1016/S0169-328X(02)00544-2.
Van der Knaap MS, Valk J. Magnetic resonance of myelin, myelination and myelin disorders. 2nd ed. Berlin: Springer; 1995.
Oakey RE. The progressive increase in oestrogen production in human pregnancy: an appraisal of the factors responsible. Vitam Horm. 1970;28:1.
Levitz M, Young BK. Estrogens in pregnancy. Vitam Horm. 1977;35:109.
Brann DW, Dhandapani K, Wakade C, Mahesh VB, Khan MM. Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids. 2007;72:381– 405. https://doi.org/10.1016/j.steroids.2007.02.003.
McCarty MM. Estradiol and the developing brain. Physiol Rev. 2008;88(1):91–124.
Lee HS, Han J, Baim HJ, Kim KW. Brain angiogenesis in developmental and pathological processes: regulation, molecular and cellular communication at the neurovascular interface. FEBS J. 2009;276(17):4622–35. https://doi.org/10.1111/j.1742-4658.2009.07174.x.
Park JA, Choi KS, Kim SY, Kim KW. Coordinated interaction of the vascular and nervous systems: from molecule-to cell-based approaches. Biochem Biophys Res Commun. 2003;311:247–53. https://doi.org/10.1016/j.bbrc.2003.09.129.
Gordon GR, Mulligan SJ, MacVicar BA. Astrocyte control of the cerebrovasculature. Glia. 2007;55:1214–21. https://doi.org/10.1002/glia.20543.
Mulligan SJ, MacVicar BA. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature. 2004;431:195–9. https://doi.org/10.1038/nature02827.
Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci. 2003;6:43–50. https://doi.org/10.1038/nn980.
Krause DN, Duckles SP, Pelligrino DA. Influence of sex steroid hormones on cerebrovascular function. J Appl Physiol. 2006;101(4):1252–61. https://doi.org/10.1152/japplphysiol.01095.2005.
Barouk S, Hintz T, Li P, Duffy AM, MacLusky NJ, Scharfman HE. 17β-estradiol increases astrocytic vascular endothelial growth factor (VEGF) in adult female rat hippocampus. Endocrinology. 2011;152(5):1745–51. https://doi.org/10.1210/en.2010-1290.
Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A. 2002;99(18):11946– 50. https://doi.org/10.1073/pnas.182296499.
Zhu Y, Jin K, Mao XO, Greenberg DA. Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. FASEB J. 2003;17(2):186–93. https://doi.org/10.1096/fj.02-0515com.
Ogunshola OO, Stewart WB, Mihalcik V, Solli T, Madri JA, Ment LR. Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain. Brain Res Dev Brain Res. 2000;119(1):139–53. https://doi.org/10.1016/S0165-3806(99)00125-X.
Haigh JJ, Morelli PI, Gerhardt H, Haigh K, Tsien J, Damert A, et al. Cortical and retinal defects caused by dosage-dependent reductions in VEGFA paracrine signaling. Dev Biol. 2003;262:225–41. https://doi.org/10.1016/S0012-1606(03)00356-7.
Raab S, Beck H, Gaumann A, Yüce A, Gerber HP, Plate K, et al. Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb Haemost. 2004;91:595–605. https://doi.org/10.1160/TH03-09-0582.
Wise PM. Estrogens and neuroprotection. Trends Endocrinol Metab. 2002;6:229–30.
Dubal DB, Wisel PM. Estrogen and neuroprotection: from clinical observations to molecular mechanisms. Dialogues Clin Neurosci. 2002;4(2):149–61.
Cho JJ, Iannucci FA, Fraile M, Franco J, Alesius TN, Stefano GB. The role of the estrogen in neuroprotection: implications for neurodegenerative diseases. Neuro Endocrinol Lett. 2003;24:141–7.
Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuroprotection by estradiol. Prog Neurobiol. 2001;63:29–60. https://doi.org/10.1016/S0301-0082(00)00025-3.
Gold SM, Voskuhl RR. Estrogen treatment in multiple sclerosis. J Neurol Sci. 2009;286(1– 2):99–103. https://doi.org/10.1016/j.jns.2009.05.028.
Samantaray S, Matzelle DD, Ray SK, Banik NL. Physiological low dose of estrogen-protected neurons in experimental spinal cord injury. Ann N Y Acad Sci. 2010;1199:86–9. https://doi. org/10.1111/j.1749-6632.2009.05360.x.
Suzuki S, Brown CM, Wise PM. Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol. 2009;30:201–11. https://doi.org/10.1016/j.yfrne.2009.04.007.
Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA, MIRAGE study Group. Postmenopausal hormone therapy and Alzheimer’s disease risk: interaction with age. J Neurol Neurosurg Psychiatry. 2005;76:103–5. https://doi.org/10.1136/jnnp.2003.024927.
Currie LJ, Harrison MB, Trugman JM, Bennett JP, Wooten JF. Postmenopausal estrogen use affects risk for Parkinson disease. Arch Neurol. 2004;61:886–8. https://doi.org/10.1001/archneur.61.6.886.
Gardiner SA, Morrison MF, Mozley PD, Mozley LH, Brensinger C, Bilker W. Pilot study on the effect of estrogen replacement therapy on brain dopamine transporter availability in healthy, postmenopausal women. Am J Geriatr Psychiatry. 2004;12:621–30. https://doi. org/10.1176/appi.ajgp.12.6.621.
Li R, Shen Y, Yang LB, Lue LF, Finch C, Rogers J. Estrogen enhances uptake of amyloid beta-protein by microglia derived from the human cortex. J Neurochem. 2000;75:1447–54. https://doi.org/10.1046/j.1471-4159.2000.0751447.x.
Xu H, Gouras GK, Greenfield JP, Vincent B, Naslund J, Mazzarelli L, et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998;4:447–51.
Kenchappa RS, Diwakar L, Annepu J, Ravindranath V. Estrogen and neuroprotection: higher constitutive expression of glutaredoxin in female mice offers protection against MPTP-mediated neurodegeneration. FASEB J. 2004;18:1102–4. https://doi.org/10.1096/fj.03-1075fje.
Ramirez AD, Liu X, Menniti FS. Repeated estradiol treatment prevents MPTP-induced dopamine depletion in male mice. Neuroendocrinology. 2003;77:223–31. https://doi. org/10.1159/000070277.
Nilsen J. Estradiol and neurodegenerative oxidative stress. Front Neuroendocrinol. 2008;9(4):463–75. https://doi.org/10.1016/j.yfrne.2007.12.005.
Zhang QG, Wang RM, Scott E, Han D, Dong Y, Tu JY, et al. C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and the critical period hypothesis of estrogen neuroprotection. Proc Natl Acad Sci U S A. 2011;108:E617– E24. https://doi.org/10.1093/brain/awt046.
Arevalo MA, Santos-Galindo M, Bellini M, Azcoitia I, Garcia-Segura LM. Actions of estrogens on glial cells: implications for neuroprotection. Biochim Biophys Acta. 2010;1800:1106– 12. https://doi.org/10.1016/j.bbagen.2009.10.002.
Dhandapani KM, Brann DW. Role of astrocytes in estrogen-mediated neuroprotection. Exp Gerontol. 2007;42(1–2):70–5. https://doi.org/10.1016/j.exger.2006.06.032.
Brinton RD. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. 2008;31(10):529–37. https://doi.org/10.1016/j. tins.2008.07.003.
Irwin RW, Yao J, Hamilton RT, Cadenas E, Brinton RD, Nilsen J. Progesterone and estrogen regulate oxidative metabolism in brain mitochondria. Endocrinology. 2008;149(6):3167–75. https://doi.org/10.1210/en.2007-1227.
Nilsen J, Brinton RD. Mitochondria as therapeutic targets of estrogen action in the central nervous system. Curr Drug Targets CNS Neurol Disord. 2004;3(4):297–13.
Nilsen J, Chen S, Irwin RW, Iwamoto S, Brinton RD. Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC Neurosci. 2006;7:74. https://doi.org/10.1186/1471-2202-7-74.
Nilsen J, Irwin RW, Gallaher TK, Brinton RD. Estradiol in vivo regulation of brain mitochondrial proteome. J Neurosci. 2007;27:14069–77. https://doi.org/10.1523/JNEUROSCI.4391-07.2007.
Brinton RD. Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer’s disease. Adv Drug Deliv Rev. 2008;60(13– 14):1504–11. https://doi.org/10.1016/j.addr.2008.06.003.
Sakamoto H, Matsuda K, Hosokawa K, Nishi M, Morris JF, Prossnitz ER, et al. Expression of G protein-coupled receptor-30, a G protein-coupled membrane estrogen receptor, in oxytocin neurons of the rat paraventricular and supraoptic nuclei. Endocrinology. 2007;148(12):5842– 50. https://doi.org/10.1210/en.2007-0436.
Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005;307(5715):1625–30. https://doi.org/10.1126/science.1106943.
Funakoshi T, Yanai A, Shinoda K, Kawano MM, Mizukami Y. G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane. Biochem Biophys Res Commun. 2006;46(3):904–10. https://doi.org/10.1016/j.bbrc.2006.05.191.
Xu H, Qin S, Carrasco GA, Dai Y, Filardo EJ, Prossnitz ER, et al. Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus. Neuroscience. 2009;158(4):1599– 607. https://doi.org/10.1016/j.neuroscience.2008.11.028.
Alyea RA, Laurence SE, Kim SH, Katzenellenbogen BS, Katzenellenbogen JA, Watson CS. The roles of membrane estrogen receptor subtypes in modulating dopamine transporters in PC-12 cells. J Neurochem. 2008;106(4):1525–33. https://doi. org/10.1111/j.1471-4159.2008.05491.x.
Kuhn J, Dina OA, Goswami C, Suckow V, Levine JD, Hucho T. GPR30 estrogen receptor agonists induce mechanical hyperalgesia in the rat. Eur J Neurosci. 2008;27(7):1700–9. https://doi.org/10.1111/j.1460-9568.2008.06131.x.
Qiu J, Bosch MA, Tobias SC, Krust A, Graham SM, Murphy SJ, et al. A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis. J Neurosci. 2006;26(21):5649–55. https://doi.org/10.1523/JNEUROSCI.0327-06.2006.
Delaunay F, Pettersson K, Tujague M, Gustafsson JA. Functional differences between the amino-terminal domains of estrogen receptors alpha and beta. Mol Pharmacol. 2000;58(3):584– 90. https://doi.org/10.1124/mol.58.3.584.
He S, Nelson ER. 27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator. Maturitas. 2017;104:29–35. https://doi.org/10.1016/j.maturitas.2017.07.014.
Li X, Schwartz PE, Rissman EF. Distribution of estrogen receptor β-like immunoreactivity in rat forebrain. Neuroendocrinology. 1997;66:63–7.
Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor-α and-β mRNA in the rat central nervous system. J Comp Neurol. 1997;388:507–25. https://doi. org/10.1002/(SICI)1096-9861(19971201)388:4<507::AID-CNE1>3.0.CO;2-6.
Zhang JQ, Cai WQ, Zhou de S, Su BY. Distribution and differences of estrogen receptor beta immunoreactivity in the brain of adult male and female rats. Brain Res. 2002;935(1–2):73–80. https://doi.org/10.1016/S0006-8993(02)02460-5.
Mitra SW, Hoskin E, Yudkovitz J, Pear L, Wilkinson HA, Hayashi S, et al. Immunolocalization of estrogen receptor-α in the mouse brain: comparison with estrogen receptor β. Endocrinology. 2003;144(5):2055–67. https://doi.org/10.1210/en.2002-221069.
Brinton RD. Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci. 2009;30(4):212–22. https://doi.org/10.1016/j.tips.2008.12.006.
Hajszan T, Milner TA, Leranth C. Sex steroids and the dentate gyrus. Prog Brain Res. 2007;163:399–416. https://doi.org/10.1016/S0079-6123(07)63023-4.
Dan P, Cheung JC, Scriven DR, Moore ED. Epitope-dependent localization of estrogen receptor-alpha, but not-beta, in en face arterial endothelium. Am J Physiol Heart Circ Physiol. 2003;284:H1295–306. https://doi.org/10.1152/ajpheart.00781.2002.
Mazzucco CA, Lieblich SE, Bingham BI, Williamson MA, Viau V, Galea LAM. Both estrogen receptor alpha and estrogen receptor beta agonists enhance cell proliferation in the dentate gyrus of adult female rats. Neuroscience. 2006;141(4):1793–800. https://doi.org/10.1016/j. neuroscience.2006.05.032.
Alkayed NJ, Murphy SJ, Traystman RJ, Hurn PD, Miller VM. Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke. 2000;31(1):161–8. https://doi.org/10.1161/01.STR.31.1.161.
Kuan CY, Roth KA, Flavell RA, Rakic P. Mechanisms of programmed cell death in the developing brain. Trends Neurosci. 2000;23(7):291–7. https://doi.org/10.1016/S0166-2236(00)01581-2.
Singh M. Ovarian hormones elicit phosphorylation of Akt and extracellular-signal regulated kinase in explants of the cerebral cortex. Endocrine. 2001;14(3):407–15. https://doi. org/10.1385/ENDO:14:3:407.
Zaidi AU, D’Sa-Eipper C, Brenner J, Kuida K, Zheng TS, Flavell RA, et al. Bcl-X(L)-caspase-9 interactions in the developing nervous system: evidence for multiple death pathways. J Neurosci. 2001;21(1):169–75.
Wade CB, Dorsa DM. Estrogen activation of cyclic adenosine 5′-monophosphate response element-mediated transcription requires the extracellularly regulated kinase/mitogen-activated protein kinase pathway. Endocrinology. 2003;144:832–8. https://doi.org/10.1210/en.2002-220899.
Quesada A, Micevych PE. Estrogen interacts with the IGF-1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6-hydroxydopamine lesions. J Neurosci Res. 2004;75(1):107–16. https://doi.org/10.1002/jnr.10833.
Hagen AA, Barr M, Diczfalusy E. Metabolism of 17β-oestradiol-4-14C in early infancy. Acta Endocrinol. 1965;49:207–20. https://doi.org/10.1530/acta.0.0490207.
Warmerdam EG, Visser M, Coeling Bennink HJ, Groen M. A new route of synthesis of estetrol. Climacteric. 2008;11(Suppl 1):59–63. https://doi.org/10.1080/13697130802054078.
Holinka CF, Diczfalusy E, Coeling Bennink HJTC. Estetrol: a unique steroid in human pregnancy. J Steroid Biochem Mol Biol. 2008;110(1–2):138–43. https://doi.org/10.1016/j. jsbmb.2008.03.027.
Visser M, Foidart J-M, Coelingh Bennink HJT. In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism. Climacteric. 2008;11(Suppl 1):64–8. https://doi. org/10.1080/13697130802050340.
Coeling Bennink HJTC, Skouby S, Bouchard P, Holinka CF. Ovulation inhibition by estetrol in an in vivo model. Contraception. 2008;77(3):186–90. https://doi.org/10.1016/j. contraception.2007.11.014.
Coelingh Bennink HJTC, Holinka CF, Diczfalusy E. Estetrol review: profile and potential clinical applications. Climacteric. 2008;11(Suppl 1):47–58. https://doi. org/10.1080/13697130802040077.
Hirano S, Furutama D, Hanafusa T. Physiologically high concentrations of 17beta-estradiol enhance NF-kappaB activity in human T cells. Am J Physiol Regul Integr Comp Physiol. 2007;292(4):R1465–71. https://doi.org/10.1152/ajpregu.00778.2006.
Koh KK, Yoon BK. Controversies regarding hormone therapy: insights from inflammation and hemostasis. Cardiovasc Res. 2006;70(1):22–30. https://doi.org/10.1016/j. cardiores.2005.12.004.
Herrington DM, Klein KP. Invited review: Pharmacogenetics of estrogen replacement therapy. J Appl Physiol (1985). 2001;91(6):2776–84. https://doi.org/10.1152/jappl.2001.91.6.2776.
Arnal JF, Valéra MC, Payrastre B, Lenfant F, Gourdy P. Structure-function relationship of estrogen receptors in cardiovascular pathophysiological models. Thromb Res. 2012;130(Suppl 1):S7–11. https://doi.org/10.1016/j.thromres.2012.08.261.
Deroo BJ, Korach KS. Estrogen receptors and human disease: an update. Arch Toxicol. 2012;86(10):1491–504. https://doi.org/10.1007/s00204-012-0868-5.
ACOG. Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy. Obstet Gynecol. 2014;123(4):896–901.
Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomised trial. Lancet. 2005;65(9460):663–70. https://doi.org/10.1016/S0140-6736(05)17946-X.
Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574–84. https://doi.org/10.1056/NEJMcps050929.
Robertson CM, Perlman M. Follow-up of the term infant after hypoxic-ischemic encephalopathy. Paediatr Child Health. 2006;11(5):278–82.
Zanelli SA. http://emedicine.medscape.com/article/973501-overview?src=refgatesrc1#a5. Accessed 16 Jan 2015.
Bryce J, Boschi-Pinto C, Shibuya K, Black RE, WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet. 2005;365(9465): 1147–52.
Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR, et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ. 1998;317(7172):1549–53. https://doi.org/10.1136/bmj.317.7172.1549.
Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR, et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ. 1998;317(7172):1554–8. https://doi.org/10.1136/bmj.317.7172.1554.
Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol. 2008;199(6):587–95. https://doi.org/10.1016/j.ajog.2008.06.094.
Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron. 1995;15(4):961–73. https://doi.org/10.1016/0896-6273(95)90186-8.
Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87(1):315–424. https://doi.org/10.1152/physrev.00029.2006.
Chang YC, Huang CC. Perinatal brain injury and regulation of transcription. Curr Opin Neurol. 2006;19(2):141–7. https://doi.org/10.1097/01.wco.0000218229.73678.a8.
Domoki F, Kis B, Nagy K, Farkas E, Busija DW, Bari F. Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets. Am J Physiol Heart Circ Physiol. 2005;289:H368–73. https://doi.org/10.1152/ajpheart.00887.2004.
Gerosa C, Fanni D, Puddu M, Locci G, Obinu E, Fanos V, et al. Histological markers of neonatal asphyxia: the relevant role of vascular changes. J Pediatr Neonat Individual Med. 2014;3(2):e030275.
Olah O, Toth-Szuki V, Temesvari P, Bari F, Domoki F. Delayed neurovascular dysfunction is alleviated by hydrogen in asphyxiated newborn pigs. Neonatology. 2013;104:79–86. https://doi.org/10.1159/000348445.
Ireland Z, Castillo-Melendez M, Dickinson H, Snow R, Walker DW. A maternal diet supplemented with creatine from mid-pregnancy protects the newborn spiny mouse brain from birth hypoxia. Neuroscience. 2011;194:372–9. https://doi.org/10.1016/j. neuroscience.2011.05.012.
Fleiss B, Coleman HA, Castillo-Melendez M, Ireland Z, Walker DW, Parkington HC. Effects of birth asphyxia on neonatal hippocampal structure and function in the spiny mouse. Int J Dev Neurosci. 2011;29:757–66. https://doi.org/10.1016/j.ijdevneu.2011.05.006.
Schiering IA, de Haan TR, Niermeijer JM, Koelman JH, Majoie CB, Reneman L, et al. Correlation between clinical and histologic findings in the human neonatal hippocampus after perinatal asphyxia. J Neuropathol Exp Neurol. 2014;73:324–34. https://doi.org/10.1097/NEN.0000000000000056.
Okereafor A, Allsop J, Counsell SJ, Fitzpatrick J, Azzopardi D, Rutherford MA, et al. Patterns of brain injury in neonates exposed to perinatal sentinel events. Pediatrics. 2008;121(5):906– 14. https://doi.org/10.1542/peds.2007-0770.
Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol. 1976;33(10):696–705. https://doi.org/10.1001/archneur.1976.00500100030012.
Douglas-Escobar M, Weiss MD. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 2015;169(4):397–403. https://doi.org/10.1001/jamapediatrics.2014.3269.
Thoresen M, Hellstrom-Westas L, Liu X, de Vries LS. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics. 2010;126(1):e131–9. https://doi.org/10.1542/peds.2009-2938.
Rothermundt M, Peters M, Prehn JH, Arolt V. S100B in brain damage and neurodegeneration. Microsc Res Tech. 2003;60(6):614–32. https://doi.org/10.1002/jemt.10303.
Ennen CS, Huisman TA, Savage WJ, Northington FJ, Jennings JM, Everett AD, et al. Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole-body cooling. Am J Obstet Gynecol. 2005;205(3):251.e1–7. https://doi. org/10.1016/j.ajog.2011.06.025.
Shankaran S. The postnatal management of the asphyxiated term infant. Clin Perinatol. 2002;29(4):675–92.
Stola A, Perlman J. Post-resuscitation strategies to avoid ongoing injury following intrapartum hypoxia-ischemia. Semin Fetal Neonatal Med. 2008;13(6):424–31. https://doi. org/10.1016/j.siny.2008.04.011.
Hoehn T, Hansmann G, Bührer C, Simbruner G, Gunn AJ, Yager J, et al. Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units. Resuscitation. 2008;78:7–12. https://doi.org/10.1016/j.resuscitation.2008.04.027.
Thoresen M, Tooley J, Liu X, Jary S, Fleming P, Luyt K, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology. 2013;104(3):228–33. https://doi.org/10.1159/000353948.
Edwards DA, Azzopardi DV, Gunn AJ. Neonatal neural rescue: a clinical guide. Cambridge, UK: Cambridge University Press; 2013.
Ballot DE. Cooling for newborns with hypoxic ischaemic encephalopathy: RHL commentary (last revised: 1 October 2010). The WHO Reproductive Health Library. Geneva: World Health Organization (WHO).
Zanelli S, Buck M, Fairchild K. Physiologic and pharmacologic considerations for hypothermia therapy in neonates. J Perinatol. 2011;31(6):377–86. https://doi.org/10.1038/jp.2010.146.
Thoresen M, Whitelaw A. Therapeutic hypothermia for hypoxic-ischaemic encephalopathy in the newborn infant. Curr Opin Neurol. 2005;18(2):111–6. https://doi.org/10.1097/01. wco.0000162850.44897.c6.
Tskitishvili E, Nisolle M, Munaut C, Pequeux C, Gerard C, Noel A, et al. Neonatal estetrol attenuates neonatal hypoxic-ischemic brain injury. Exp Neurol. 2014;261:298–307. https://doi.org/10.1016/j.expneurol.2014.07.015.
Tskitishvili E, Pequeux C, Munaut C, Viellevoye R, Nisolle M, Noël A, et al. 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. https://doi.org/10.18632/oncotarget.9591.
Tskitishvili E, Pequeux C, Munaut C, Viellevoye R, Nisolle M, Noël A, et al. Estrogen receptors and estetrol-dependent neuroprotective actions: a pilot study. J Endocrinol. 2017;232(1):85–95. https://doi.org/10.1530/JOE-16-0434.
Johnson GV, Jope RS. The role of microtubule-associated protein 2 (MAP-2) in neuronal growth, plasticity, and degeneration. J Neurosci Res. 1992;33(4):505–12. https://doi. org/10.1002/jnr.490330402.
Bartosik-Psujek H, Stelmasiak Z. Biochemical markers of damage of the central nervous system in multiple sclerosis. Ann Univ Mariae Curie Sklodowska Med. 2001;56:389–92.
Roof RL, Duvdevani R, Braswell L, Stein DG. Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Exp Neurol. 1994;129:64–9. https://doi.org/10.1006/exnr.1994.1147.
Roof RL, Hoffman SW, Stein DG. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol. 1997;31(1):1–11.
Roof RL, Hall E. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma. 2000;17(5):367–88. https://doi.org/10.1089/neu.2000.17.367.
Stein D. Brain damage, sex hormones and recovery: a new role for progesterone and estrogen? Trends Neurosci. 2001;24(7):386–91. https://doi.org/10.1016/S0166-2236(00)01821-X.
Gold SM, Voskuhl RR. Estrogen and testosterone therapies in multiple sclerosis. Prog Brain Res. 2009;175:239–51. https://doi.org/10.1016/S0079-6123(09)17516-7.
Kaur P, Jodhka PK, Underwood WA, Bowles CA, de Fiebre NC, de Fiebre CM, et al. Progesterone increases brain-derived neurotrophic factor expression and protects against glutamate toxicity in a mitogen-activated protein kinase-and phosphoinositide-3 kinase-dependent manner in cerebral cortical explants. J Neurosci Res. 2007;85(11):2441–9. https://doi.org/10.1002/jnr.21370.
Nilsen J, Brinton RD. Impact of progestins on estradiol potentiation of the glutamate calcium response. Neuroreport. 2002;13(6):825–30.
Nilsen J, Brinton RD. Impact of progestins on estrogen induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology. 2002;143(1):205–12. https://doi.org/10.1210/endo.143.1.8582.
Nilsen J, Brinton RD. Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen activated protein kinase signaling. Proc Natl Acad Sci U S A. 2003;100(18):10506–11. https://doi.org/10.1073/pnas.1334098100.
Goodman Y, Bruce AJ, Cheng B, Mattson MP. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem. 1996;66:1836–44. https://doi.org/10.1046/j.1471-4159.1996.66051836.x.
Singh M, Su C. Progesterone and neuroprotection. Horm Behav. 2013;63(2):284–90. https://doi.org/10.1016/j.yhbeh.2012.06.003.
Trotter A, Steinmacher J, Kron M, Pohlandt F. Neurodevelopmental follow-up at five years corrected age of extremely low birth weight infants after postnatal replacement of 17-estradiol and progesterone. J Clin Endocrinol Metab. 2012;97(3):1041–7. https://doi.org/10.1210/jc.2011-2612.
Lorenz L, Dang J, Misiak M, Tameh Abolfazl A, Beyer C, Kipp M. Combined 17beta-oestradiol and progesterone treatment prevents neuronal cell injury in cortical but not midbrain neurones or neuroblastoma cells. J Neuroendocrinol. 2009;21(10):841–9. https://doi.org/10.1111/j.1365-2826.2009.01903.x.
Mannella P, Sanchez AM, Giretti MS, Genazzani AR, Simoncini T. Oestrogen and progestins differently prevent glutamate toxicity in cortical neurons depending on prior hormonal exposure via the induction of neural nitric oxide synthase. Steroids. 2009;74(8):650–6. https://doi. org/10.1210/me.2008-0408.
Aguirre CC, Baudry M. Progesterone reverses 17betaestradiol-mediated neuroprotection and BDNF induction in cultured hippocampal slices. Eur J Neurosci. 2009;29(3):447–54. https://doi.org/10.1111/j.1460-9568.2008.06591.x.
Aguirre C, Jayaraman A, Pike C, Baudry M. Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-beta. J Neurochem. 2010;115(5):1277–87. https://doi.org/10.1111/j.1471-4159.2010.07038.x.
Carroll JC, Rosario ER, Pike CJ. Progesterone blocks estrogen neuroprotection from kain-ate in middle-aged female rats. Neurosci Lett. 2008;445(3):229–32. https://doi.org/10.1016/j. neulet.2008.09.010.
Jayaraman A, Pike CJ. Progesterone attenuates oestrogen neuroprotection via downregulation of oestrogen receptor expression in cultured neurones. J Neuroendocrinol. 2009;21(1):77–81. https://doi.org/10.1111/j.1365-2826.2008.01801.x.
Rosario ER, Ramsden M, Pike CJ. Progestins inhibit the neuroprotective effects of estrogen in rat hippocampus. Brain Res. 2006;1099(1):206–10. https://doi.org/10.1016/j. brainres.2006.03.127.
Yao J, Chen S, Cadenas E, Brinton RD. Estrogen protection against mitochondrial toxin-induced cell death in hippocampal neurons: antagonism by progesterone. Brain Res. 2011;1379:2–10. https://doi.org/10.1016/j.brainres.2010.11.090.
Gibson C, Constantin D, Prior M, Bath P, Murphy S. Progesterone suppresses the inflammatory response and nitric oxide synthase-2 expression following cerebral ischemia. Exp Neurol. 2005;193(2):522–30. https://doi.org/10.1016/j.expneurol.2005.01.009.
Grossman K, Goss C, Stein D. Effects of progesterone on the inflammatory response to brain injury in the rat. Brain Res. 2004;1008(1):29–39. https://doi.org/10.1016/j. brainres.2004.02.022.
Labombarda F, Gonzalez S, Gonzalez Deniselle MC, Garay L, Guennoun R, Schumacher M, et al. Progesterone increases the expression of myelin basic protein and the number of cells showing NG2 immunostaining in the lesioned spinal cord. J Neurotrauma. 2006;23(2): 181–92. https://doi.org/10.1089/neu.2006.23.181.
Pierson RC, Lyons AM, Greenfield LJ Jr. Gonadal steroids regulate GABAA receptor subunit mRNA expression in NT2-Nneurons. Brain Res Mol Brain Res. 2005;138(2):105–15. https://doi.org/10.1016/j.molbrainres.2004.10.047.
Mani SK. Signaling mechanisms in progesterone neurotransmitter interactions. Neuroscience. 2006;138(3):773–81. https://doi.org/10.1016/j.neuroscience.2005.07.034.
Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005;1049(1):112–9. https://doi.org/10.1016/j.brainres.2005.05.004.
Quadros PS, Pfau JL, Wagner CK. Distribution of progesterone receptor immunoreactivity in the fetal and neonatal rat forebrain. J Comp Neurol. 2007;504(1):42–56.
Jahagirdar V, Wagner CK. Ontogeny of progesterone receptor expression in the subplate of fetal and neonatal rat cortex. Cereb Cortex. 2010;20(5):1046–52. https://doi.org/10.1002/cne.21427.
Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014;6(10):1328–46. https://doi. org/10.15252/emmm.201404112.
La Rosa P, Pesiri V, Leclerq G, Marino M, Acconcia F. Palmitoylation regulates 17β-estradiol-induced estrogen receptor-α degradation and transcriptional activity. Mol Endocrinol. 2012;26(5):762–74. https://doi.org/10.1210/me.2011-1208.
Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M. S-palmitoylation modulates human estrogen receptor-alpha functions. Biochem Biophys Res Commun. 2004;316:878–83. https://doi.org/10.1016/j.bbrc.2004.02.129.
Khalaj AJ, Yoon J, Nakai J, Winchester Z, Moore SM, Yoo T, et al. Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand. Proc Natl Acad Sci U S A. 2013;110(47):19125–30. https://doi.org/10.1073/pnas.1311763110.
Prokai L, Prokai-Tatrai K, Perjesi P, Simpkins JW. Mechanistic insights into the direct anti-oxidant effects of estrogens. Drug Dev Res. 2005;66(2):118–25. https://doi.org/10.1002/ddr.20050.
Hammes SR, Levin ER. Extranuclear steroid receptors: nature and actions. Endocr Rev. 2007;28:726–41. https://doi.org/10.1210/er.2007-0022.
Suzuki S, Gerhold LM, Bottner M, Rau SW, Dela Cruz C, Yang E, et al. Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors a and b. J Comp Neurol. 2007;500:1064–75. https://doi.org/10.1002/cne.21240.
Spence RD, Hamby ME, Umeda E, Itoh N, Du S, Wisdom AJ, et al. Neuroprotection mediated through estrogen receptor-α in astrocytes. Proc Natl Acad Sci U S A. 2011;108:8867–72. https://doi.org/10.1073/pnas.1103833108.