The neuroprotective actions of oestradiol and oestrogen receptors

Hormones regulate homeostasis by communicating through the bloodstream to the body's organs, including the brain. As homeostatic regulators of brain function, some hormones exert neuroprotective actions. This is the case for the ovarian hormone 17β-oestradiol, which signals through oestrogen receptors (ERs) that are widely distributed in the male and female brain. Recent discoveries have shown that oestradiol is not only a reproductive hormone but also a brain-derived neuroprotective factor in males and females and that ERs coordinate multiple signalling mechanisms that protect the brain from neurodegenerative diseases, affective disorders and cognitive decline.

[1]  L. Garcia-Segura,et al.  Selective estrogen receptor modulators decrease reactive astrogliosis in the injured brain: effects of aging and prolonged depletion of ovarian hormones. , 2009, Endocrinology.

[2]  R. Brinton,et al.  Estrogen: A master regulator of bioenergetic systems in the brain and body , 2014, Frontiers in Neuroendocrinology.

[3]  L. Garcia-Segura,et al.  Antidepressive and anxiolytic activity of selective estrogen receptor modulators in ovariectomized mice submitted to chronic unpredictable stress , 2012, Behavioural Brain Research.

[4]  A. Maggi,et al.  17β-Estradiol Inhibits Inflammatory Gene Expression by Controlling NF-κB Intracellular Localization , 2005, Molecular and Cellular Biology.

[5]  F. Gage,et al.  Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta. , 2007, The Journal of comparative neurology.

[6]  L. Garcia-Segura,et al.  Behavioral effects of estradiol therapy in ovariectomized rats depend on the age when the treatment is initiated , 2012, Experimental Gerontology.

[7]  C. Behl,et al.  Glycogen synthase kinase 3β links neuroprotection by 17β-estradiol to key Alzheimer processes , 2005, Neuroscience.

[8]  Dong-Sun Han,et al.  Estrogen Attenuates Ischemic Oxidative Damage via an Estrogen Receptor α-Mediated Inhibition of NADPH Oxidase Activation , 2009, The Journal of Neuroscience.

[9]  C. J. Saldanha,et al.  Induced Synthesis of Oestrogens by Glia in the Songbird Brain , 2013, Journal of neuroendocrinology.

[10]  L. Garcia-Segura,et al.  Gonadal hormones affect neuronal vulnerability to excitotoxin-induced degeneration , 1999, Journal of neurocytology.

[11]  M. E. Brocca,et al.  Increased aromatase expression in the hippocampus of spontaneously hypertensive rats: effects of estradiol administration , 2011, Neuroscience.

[12]  L. Garcia-Segura,et al.  Endogenous estrogen formation is neuroprotective in model of cerebellar ataxia , 2003, Endocrine.

[13]  R. Vierk,et al.  Aromatase Inhibition Abolishes LTP Generation in Female But Not in Male Mice , 2012, The Journal of Neuroscience.

[14]  L. Garcia-Segura,et al.  Phosphatidylinositol 3-kinase and glycogen synthase kinase 3 regulate estrogen receptor-mediated transcription in neuronal cells. , 2006, Endocrinology.

[15]  F. Sohrabji,et al.  The Neurotoxic Effects of Estrogen on Ischemic Stroke in Older Female Rats Is Associated with Age-Dependent Loss of Insulin-Like Growth Factor-1 , 2010, The Journal of Neuroscience.

[16]  Post-ischemic estradiol treatment reduced glial response and triggers distinct cortical and hippocampal signaling in a rat model of cerebral ischemia , 2012, Journal of Neuroinflammation.

[17]  J. Simpkins,et al.  Aromatase is increased in astrocytes in the presence of elevated pressure. , 2011, Endocrinology.

[18]  D. Brann,et al.  Role of Dickkopf-1, an Antagonist of the Wnt/β-Catenin Signaling Pathway, in Estrogen-Induced Neuroprotection and Attenuation of Tau Phosphorylation , 2008, The Journal of Neuroscience.

[19]  S. Poduslo,et al.  CYP19 haplotypes increase risk for Alzheimer’s disease , 2006, Journal of Medical Genetics.

[20]  B. Nelson,et al.  Antagonism of brain insulin-like growth factor-1 receptors blocks estradiol effects on memory and levels of hippocampal synaptic proteins in ovariectomized rats , 2013, Psychopharmacology.

[21]  C. Saldanha,et al.  Inhibition of hippocampal aromatization impairs spatial memory performance in a male songbird. , 2013, Endocrinology.

[22]  D. Lindholm,et al.  Estrogen receptor-dependent regulation of sensory neuron survival in developing dorsal root ganglion. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  G. Ball,et al.  Rapid control of male typical behaviors by brain-derived estrogens , 2012, Frontiers in Neuroendocrinology.

[24]  H. Vaudry,et al.  Neurosteroid biosynthesis: Enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides , 2009, Frontiers in Neuroendocrinology.

[25]  W. Lasoń,et al.  Neuroprotective action of raloxifene against hypoxia-induced damage in mouse hippocampal cells depends on ERα but not ERβ or GPR30 signalling , 2015, The Journal of Steroid Biochemistry and Molecular Biology.

[26]  Khadija Iqbal,et al.  Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[27]  R. Zukin,et al.  Estrogen Can Act via Estrogen Receptor α and β to Protect Hippocampal Neurons against Global Ischemia-Induced Cell Death , 2005 .

[28]  L. Garcia-Segura,et al.  Comparison of plasma and cerebrospinal fluid levels of neuroactive steroids with their brain, spinal cord and peripheral nerve levels in male and female rats , 2013, Psychoneuroendocrinology.

[29]  G. Gillies,et al.  Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines , 2010, Pharmacological Reviews.

[30]  R. Brinton,et al.  Ovariectomy Induces a Shift in Fuel Availability and Metabolism in the Hippocampus of the Female Transgenic Model of Familial Alzheimer's , 2013, PloS one.

[31]  R. Vadlamudi,et al.  Estrogen neuroprotection and the critical period hypothesis , 2012, Frontiers in Neuroendocrinology.

[32]  D. Brann,et al.  Extranuclear Estrogen Receptors Mediate the Neuroprotective Effects of Estrogen in the Rat Hippocampus , 2010, PloS one.

[33]  L. Garcia-Segura,et al.  Estrogen receptor alpha forms estrogen-dependent multimolecular complexes with insulin-like growth factor receptor and phosphatidylinositol 3-kinase in the adult rat brain. , 2003, Brain research. Molecular brain research.

[34]  Dong-Sun Han,et al.  Long-term estrogen deprivation leads to elevation of Dickkopf-1 and dysregulation of Wnt/β-Catenin signaling in hippocampal CA1 neurons , 2013, Steroids.

[35]  J. Ávila,et al.  Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3, and beta-catenin in the hippocampus , 2004, Molecular and Cellular Neuroscience.

[36]  P. Shughrue,et al.  Estradiol Modulates bcl-2 in Cerebral Ischemia: A Potential Role for Estrogen Receptors , 1999, The Journal of Neuroscience.

[37]  G. Terstappen,et al.  Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1 , 2006, Neurobiology of Disease.

[38]  M. Caruso,et al.  Glia mediates the neuroprotective action of estradiol on beta-amyloid-induced neuronal death. , 2004, Endocrinology.

[39]  B. Sherwin,et al.  Estrogen and cognitive functioning in women. , 2003, Endocrine reviews.

[40]  Gang Chen,et al.  Tamoxifen as an effective neuroprotectant against early brain injury and learning deficits induced by subarachnoid hemorrhage: possible involvement of inflammatory signaling , 2013, Journal of Neuroinflammation.

[41]  J. Sastre,et al.  Oestradiol or genistein rescues neurons from amyloid beta‐induced cell death by inhibiting activation of p38 , 2008, Aging cell.

[42]  L. Garcia-Segura,et al.  Administration of an inhibitor of estrogen biosynthesis facilitates working memory acquisition in male rats , 2007, Neuroscience Research.

[43]  J. Simpkins,et al.  Neuroprotection and Estrogen Receptors , 2012, Neuroendocrinology.

[44]  C. Saldanha,et al.  Inhibition of injury‐induced glial aromatase reveals a wave of secondary degeneration in the songbird brain , 2008, Glia.

[45]  Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury , 2001 .

[46]  L. Garcia-Segura,et al.  Estradiol upregulates Bcl‐2 expression in adult brain neurons , 1998, Neuroreport.

[47]  M. Morissette,et al.  Raloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice , 2014, Neurobiology of Aging.

[48]  E. Corder,et al.  Polymorphisms in the CYP19 gene confer increased risk for Alzheimer disease , 2004, Neurology.

[49]  L. Gollapudi,et al.  Estrogen and NGF synergistically protect terminally differentiated, ERα‐transfected PC12 cells from apoptosis , 1999, Journal of neuroscience research.

[50]  J. D. del Río,et al.  Glycogen Synthase Kinase 3 Beta (GSK3β) at the Tip of Neuronal Development and Regeneration , 2013, Molecular Neurobiology.

[51]  M. Horne,et al.  Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors , 2014, PloS one.

[52]  J. G. Yague,et al.  Selective transcriptional regulation of aromatase gene by vitamin D, dexamethasone, and mifepristone in human glioma cells , 2009, Endocrine.

[53]  Rui Li,et al.  Estrogen provides neuroprotection against activated microglia‐induced dopaminergic neuronal injury through both estrogen receptor‐α and estrogen receptor‐β in microglia , 2005 .

[54]  D. Brann,et al.  Role of astrocytes in estrogen-mediated neuroprotection , 2007, Experimental Gerontology.

[55]  D. Dorsa,et al.  Modulation of Bcl‐2 expression: a potential component of estrogen protection in NT2 neurons , 1998, Neuroreport.

[56]  N. Alkayed,et al.  CALL FOR PAPERS Sex and Gender Differences in Cardiovascular Physiology—Back to the Basics Role of aromatase in sex-specific cerebrovascular endothelial function in mice , 2014 .

[57]  H. Carswell,et al.  Neuroprotection by a selective estrogen receptor beta agonist in a mouse model of global ischemia. , 2004, American journal of physiology. Heart and circulatory physiology.

[58]  L. Sherman,et al.  Treatment with selective estrogen receptor modulators regulates myelin specific T‐cells and suppresses experimental autoimmune encephalomyelitis , 2009, Glia.

[59]  David A. Bennett,et al.  REST and Stress Resistance in Aging and Alzheimer’s Disease , 2014, Nature.

[60]  H. B. Fokidis,et al.  Regulation of local steroidogenesis in the brain and in prostate cancer: Lessons learned from interdisciplinary collaboration , 2015, Frontiers in Neuroendocrinology.

[61]  S. Callier,et al.  Estrogen and SERM neuroprotection in animal models of Parkinson's disease , 2008, Molecular and Cellular Endocrinology.

[62]  J. Morrison,et al.  Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[63]  J. Rodríguez-Orengo,et al.  Tamoxifen and estradiol improved locomotor function and increased spared tissue in rats after spinal cord injury: Their antioxidant effect and role of estrogen receptor alpha , 2014, Brain Research.

[64]  D. Clegg,et al.  The role of hypothalamic estrogen receptors in metabolic regulation , 2014, Frontiers in Neuroendocrinology.

[65]  M. Castelló-Ruiz,et al.  The selective estrogen receptor modulator, bazedoxifene, reduces ischemic brain damage in male rat , 2014, Neuroscience Letters.

[66]  Jing Xu,et al.  Inhibition of MLK3‐MKK4/7‐JNK1/2 pathway by Akt1 in exogenous estrogen‐induced neuroprotection against transient global cerebral ischemia by a non‐genomic mechanism in male rats , 2006, Journal of neurochemistry.

[67]  I. Torres-Aleman,et al.  Trophic effects of estradiol on fetal rat hypothalamic neurons. , 1992, Neuroendocrinology.

[68]  G. Meyer,et al.  VDAC and ERα interaction in caveolae from human cortex is altered in Alzheimer's disease , 2009, Molecular and Cellular Neuroscience.

[69]  R. Zukin,et al.  Acute Administration of Non-Classical Estrogen Receptor Agonists Attenuates Ischemia-Induced Hippocampal Neuron Loss in Middle-Aged Female Rats , 2010, PloS one.

[70]  Rena Li,et al.  Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[71]  P. Chambon,et al.  Estrogen receptor-α mediates the brain antiinflammatory activity of estradiol , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[72]  L. McCullough,et al.  Aromatase Cytochrome P450 and Extragonadal Estrogen Play a Role in Ischemic Neuroprotection , 2003, The Journal of Neuroscience.

[73]  Stephen Safe,et al.  Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways. , 2008, Journal of molecular endocrinology.

[74]  Lauren C Harte-Hargrove,et al.  Brain-derived neurotrophic factor–estrogen interactions in the hippocampal mossy fiber pathway: Implications for normal brain function and disease , 2013, Neuroscience.

[75]  S. Chongthammakun,et al.  A priming role of local estrogen on exogenous estrogen-mediated synaptic plasticity and neuroprotection , 2012, Experimental & Molecular Medicine.

[76]  L. Doncarlos,et al.  Glia-neuron crosstalk in the neuroprotective mechanisms of sex steroid hormones , 2005, Brain Research Reviews.

[77]  L. Garcia-Segura,et al.  An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin‐like growth factor‐I in the dentate gyrus of adult female rat , 2003, The European journal of neuroscience.

[78]  A. Wu,et al.  Raloxifene Suppresses Experimental Autoimmune Encephalomyelitis and NF-κB-Dependent CCL20 Expression in Reactive Astrocytes , 2014, PloS one.

[79]  T. Di Paolo,et al.  Implication of the Phosphatidylinositol-3 Kinase/Protein Kinase B Signaling Pathway in the Neuroprotective Effect of Estradiol in the Striatum of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mice , 2006, Molecular Pharmacology.

[80]  R. Zukin,et al.  Effects of global ischemia and estradiol pretreatment on phosphorylation of Akt, CREB and STAT3 in hippocampal CA1 of young and middle-aged female rats , 2012, Brain Research.

[81]  A. Walf,et al.  Raloxifene and/or estradiol decrease anxiety-like and depressive-like behavior, whereas only estradiol increases carcinogen-induced tumorigenesis and uterine proliferation among ovariectomized rats , 2010, Behavioural pharmacology.

[82]  Roberta Diaz Brinton,et al.  Mechanism of estrogen-mediated neuroprotection: Regulation of mitochondrial calcium and Bcl-2 expression , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[83]  P. Evans,et al.  Mechanisms underlying the interactions between rapid estrogenic and BDNF control of synaptic connectivity , 2013, Neuroscience.

[84]  L. Doncarlos,et al.  Neuroprotective actions of selective estrogen receptor modulators , 2009, Psychoneuroendocrinology.

[85]  V. Papadopoulos,et al.  Mitochondrial protein import and the genesis of steroidogenic mitochondria , 2011, Molecular and Cellular Endocrinology.

[86]  X. Wang,et al.  Estrogen receptor alpha and G-protein coupled receptor 30 mediate the neuroprotective effects of 17β-estradiol in novel murine hippocampal cell models , 2010, Neuroscience.

[87]  M. Yao,et al.  Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against β-Amyloid Peptide-Induced Neuronal Death , 2007, The Journal of Neuroscience.

[88]  L. Garcia-Segura,et al.  Notch/Neurogenin 3 Signalling is Involved in the Neuritogenic Actions of Oestradiol in Developing Hippocampal Neurones , 2011, Journal of neuroendocrinology.

[89]  J. Shine,et al.  Sequence and expression of human estrogen receptor complementary DNA. , 1986, Science.

[90]  Shuyan Wang,et al.  17β-Estradiol Protects Dopaminergic Neurons in Organotypic Slice of Mesencephalon by MAPK-Mediated Activation of Anti-apoptosis Gene BCL2 , 2011, Journal of Molecular Neuroscience.

[91]  A. Eckert,et al.  Sciatic nerve injury induces apoptosis of dorsal root ganglion satellite glial cells and selectively modifies neurosteroidogenesis in sensory neurons , 2010, Glia.

[92]  Yaakov Stern,et al.  Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease , 1996, The Lancet.

[93]  L. Garcia-Segura,et al.  Selective estrogen receptor modulators regulate reactive microglia after penetrating brain injury , 2014, Front. Aging Neurosci..

[94]  M. Mena,et al.  Gender differences and estrogen effects in parkin null mice , 2008, Journal of neurochemistry.

[95]  K. Yaffe,et al.  Timing of hormone therapy and dementia: The critical window theory revisited , 2011, Annals of neurology.

[96]  L. Garcia-Segura,et al.  G protein-coupled estrogen receptor is required for the neuritogenic mechanism of 17β-estradiol in developing hippocampal neurons , 2013, Molecular and Cellular Endocrinology.

[97]  F. Gage,et al.  Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors α and β , 2007 .

[98]  Michael Schoen,et al.  Gonadotropin-releasing hormone regulates spine density via its regulatory role in hippocampal estrogen synthesis , 2008, The Journal of cell biology.

[99]  H. Onoe,et al.  11C-Cetrozole: An Improved C-11C-Methylated PET Probe for Aromatase Imaging in the Brain , 2014, The Journal of Nuclear Medicine.

[100]  R. Vadlamudi,et al.  Brain-derived estrogen exerts anti-inflammatory and neuroprotective actions in the rat hippocampus , 2014, Molecular and Cellular Endocrinology.

[101]  L. Garcia-Segura,et al.  Selective estrogen receptor modulators as brain therapeutic agents. , 2011, Journal of molecular endocrinology.

[102]  A. M. Etgen,et al.  Neuroprotective action of acute estrogens: Animal models of brain ischemia and clinical implications , 2013, Steroids.

[103]  J. Balthazart,et al.  Oestrogen‐deficient female aromatase knockout (ArKO) mice exhibit ‘depressive‐like’ symptomatology , 2004, The European journal of neuroscience.

[104]  L. Garcia-Segura,et al.  Neuroprotective effects of estradiol in the adult rat hippocampus: Interaction with insulin‐like growth factor‐I signalling , 1999, Journal of neuroscience research.

[105]  Roberta Diaz Brinton,et al.  Estrogen receptor α and β differentially regulate intracellular Ca2+ dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons , 2007, Brain Research.

[106]  V. Jordan,et al.  Send Orders of Reprints at Reprints@benthamscience.net the Discovery and Development of Selective Estrogen Receptor Modulators (serms) for Clinical Practice the Biological Basis of Serm Action: Target Tissue Specific Actions , 2022 .

[107]  Chandler R. L. Mongerson,et al.  Estrogen Mediates Neuroprotection and Anti-Inflammatory Effects during EAE through ERα Signaling on Astrocytes But Not through ERβ Signaling on Astrocytes or Neurons , 2013, The Journal of Neuroscience.

[108]  J. G. Yague,et al.  Estradiol synthesis within the human brain , 2011, Neuroscience.

[109]  J. Lambert,et al.  Neurosteroids: endogenous regulators of the GABAA receptor , 2005, Nature Reviews Neuroscience.

[110]  P. Deloukas,et al.  The sex-specific associations of the aromatase gene with Alzheimer’s disease and its interaction with IL10 in the Epistasis Project , 2013, European Journal of Human Genetics.

[111]  J. Simpkins,et al.  The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats. , 1995, Endocrinology.

[112]  N. Harada,et al.  Brain aromatase is neuroprotective. , 2001, Journal of neurobiology.

[113]  R. Rupprecht,et al.  The role of allopregnanolone in depression and anxiety , 2014, Progress in Neurobiology.

[114]  C. Pike,et al.  Selective estrogen receptor modulators differentially regulate Alzheimer-like changes in female 3xTg-AD mice. , 2008, Endocrinology.

[115]  T. Jover-Mengual,et al.  Acute estradiol protects CA1 neurons from ischemia-induced apoptotic cell death via the PI3K/Akt pathway , 2010, Brain Research.

[116]  D. Grandy,et al.  Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C , 2003, The Journal of Neuroscience.

[117]  A. Dominiczak,et al.  Brain aromatase expression after experimental stroke: Topography and time course , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[118]  Enrique M. Toledo,et al.  Wnt signaling in neuroprotection and stem cell differentiation , 2008, Progress in Neurobiology.

[119]  L. Garcia-Segura,et al.  Aromatase inhibition exacerbates pain and reactive gliosis in the dorsal horn of the spinal cord of female rats caused by spinothalamic tract injury. , 2014, Endocrinology.

[120]  Konrad F. Koehler,et al.  Development of subtype-selective oestrogen receptor-based therapeutics , 2011, Nature Reviews Drug Discovery.

[121]  Ana Dopazo,et al.  Estradiol Activates β-Catenin Dependent Transcription in Neurons , 2009, PloS one.

[122]  G. Callard,et al.  Localization of aromatase in synaptosomal and microsomal subfractions of quail (Coturnix coturnix japonica) brain. , 1989, Neuroendocrinology.

[123]  Dong-Sun Han,et al.  C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection , 2011, Proceedings of the National Academy of Sciences.

[124]  L. Garcia-Segura,et al.  Sex differences in the inflammatory response of primary astrocytes to lipopolysaccharide , 2011, Biology of Sex Differences.

[125]  L. Garcia-Segura,et al.  Role of estrogen receptor α in membrane-initiated signaling in neural cells: Interaction with IGF-1 receptor , 2009, The Journal of Steroid Biochemistry and Molecular Biology.

[126]  M. Pesaresi,et al.  Effect of Short‐and Long‐Term Gonadectomy on Neuroactive Steroid Levels in the Central and Peripheral Nervous System of Male and Female Rats , 2010, Journal of neuroendocrinology.

[127]  P. Maki,et al.  Critical window hypothesis of hormone therapy and cognition: a scientific update on clinical studies , 2013, Menopause.

[128]  B. Tycko,et al.  Variants in CYP17 and CYP19 cytochrome P450 genes are associated with onset of Alzheimer's disease in women with down syndrome. , 2012, Journal of Alzheimer's disease : JAD.

[129]  A. Lima,et al.  Involvement of Brain‐Derived Neurotrophic Factor and Neurogenesis in Oestradiol Neuroprotection of the Hippocampus of Hypertensive Rats , 2010, Journal of neuroendocrinology.

[130]  Christine F. Witty,et al.  Short-term estradiol administration in aging ovariectomized rats provides lasting benefits for memory and the hippocampus: a role for insulin-like growth factor-I. , 2013, Endocrinology.

[131]  L. Garcia-Segura,et al.  Role of astrocytes in the neuroprotective actions of 17β-estradiol and selective estrogen receptor modulators , 2014, Molecular and Cellular Endocrinology.

[132]  L. Doncarlos,et al.  Glial expression of estrogen and androgen receptors after rat brain injury , 2002, The Journal of comparative neurology.

[133]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[134]  D. Swaab,et al.  Neurosteroid biosynthetic pathways changes in prefrontal cortex in Alzheimer's disease , 2011, Neurobiology of Aging.

[135]  V. Luine,et al.  Interactions between estradiol, BDNF and dendritic spines in promoting memory , 2013, Neuroscience.

[136]  G. Olmos,et al.  Neuroprotective Effects of Estradiol on Motoneurons in a Model of Rat Spinal Cord Embryonic Explants , 2013, Cellular and Molecular Neurobiology.

[137]  Rena Li,et al.  Brain Endogenous Estrogen Levels Determine Responses to Estrogen Replacement Therapy via Regulation of BACE1 and NEP in Female Alzheimer’s Transgenic Mice , 2012, Molecular Neurobiology.

[138]  L. Garcia-Segura,et al.  Effects of selective estrogen receptor modulators on allocentric working memory performance and on dendritic spines in medial prefrontal cortex pyramidal neurons of ovariectomized rats , 2012, Hormones and Behavior.

[139]  Roberta Diaz Brinton,et al.  Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neurons , 2004, Brain Research.

[140]  L. Remage-Healey,et al.  Estradiol Synthesis and Action at the Synapse: Evidence for “Synaptocrine” Signaling , 2011, Front. Endocrin..

[141]  T. Jover-Mengual,et al.  MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia. , 2007, Endocrinology.

[142]  L. Garcia-Segura,et al.  Steroidogenic acute regulatory protein in the rat brain: cellular distribution, developmental regulation and overexpression after injury , 2003, The European journal of neuroscience.

[143]  S. Pandey,et al.  Effects of Estrogen Treatment on Expression of Brain-Derived Neurotrophic Factor and cAMP Response Element-Binding Protein Expression and Phosphorylation in Rat Amygdaloid and Hippocampal Structures , 2005, Neuroendocrinology.

[144]  D. Brann,et al.  Astrocyte-Derived Transforming Growth Factor-β Mediates the Neuroprotective Effects of 17β-Estradiol: Involvement of Nonclassical Genomic Signaling Pathways , 2005 .

[145]  M. Wessendorf,et al.  Spinal Synthesis of Estrogen and Concomitant Signaling by Membrane Estrogen Receptors Regulate Spinal κ- and μ-Opioid Receptor Heterodimerization and Female-Specific Spinal Morphine Antinociception , 2011, The Journal of Neuroscience.

[146]  A. Maggi,et al.  Insulin-like growth factors activate estrogen receptor to control the growth and differentiation of the human neuroblastoma cell line SK-ER3. , 1994, Molecular endocrinology.

[147]  O. Rønnekleiv,et al.  Role of Signal Transducer and Activator of Transcription-3 in Estradiol-Mediated Neuroprotection , 2007, The Journal of Neuroscience.

[148]  M. McCarthy,et al.  A developmental sex difference in hippocampal neurogenesis is mediated by endogenous oestradiol , 2010, Biology of Sex Differences.

[149]  Roberta Diaz Brinton,et al.  Estrogen Receptor Protein Interaction with Phosphatidylinositol 3-Kinase Leads to Activation of Phosphorylated Akt and Extracellular Signal-Regulated Kinase 1/2 in the Same Population of Cortical Neurons: A Unified Mechanism of Estrogen Action , 2006, The Journal of Neuroscience.

[150]  L. Garcia-Segura,et al.  Selective oestrogen receptor (ER) modulators reduce microglia reactivity in vivo after peripheral inflammation: potential role of microglial ERs. , 2008, The Journal of endocrinology.

[151]  B. Schlinger,et al.  Radial glia express aromatase in the injured zebra finch brain , 2004, The Journal of comparative neurology.

[152]  R. Zukin,et al.  Survivin Is a Transcriptional Target of STAT3 Critical to Estradiol Neuroprotection in Global Ischemia , 2013, The Journal of Neuroscience.

[153]  L. Garcia-Segura,et al.  Actions of estrogens on glial cells: Implications for neuroprotection. , 2010, Biochimica et biophysica acta.

[154]  L. McCullough,et al.  Estrogen Enhances Neurogenesis and Behavioral Recovery after Stroke , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[155]  B. Liu,et al.  Tamoxifen protects male mice nigrostriatal dopamine against methamphetamine-induced toxicity. , 2007, Biochemical pharmacology.

[156]  E. Baulieu,et al.  NEUROSTEROIDS: A NOVEL FUNCTION OF THE BRAIN , 1998, Psychoneuroendocrinology.

[157]  M. Díaz,et al.  Estradiol and tamoxifen differentially regulate a plasmalemmal voltage-dependent anion channel involved in amyloid-beta induced neurotoxicity , 2011, Steroids.

[158]  E. Mufson,et al.  Effects of aromatase inhibition versus gonadectomy on hippocampal complex amyloid pathology in triple transgenic mice , 2012, Neurobiology of Disease.

[159]  C. Léránth,et al.  Aromatase immunoreactivity in axon terminals of the vertebrate brain. An immunocytochemical study on quail, rat, monkey and human tissues. , 1996, Neuroendocrinology.

[160]  G. Rune,et al.  Para/autocrine regulation of estrogen receptors in hippocampal neurons , 2003, Hippocampus.

[161]  L. Garcia-Segura,et al.  Neuroactive steroids: State of the art and new perspectives , 2008, Cellular and Molecular Life Sciences.

[162]  Myles Brown,et al.  Cofactor Dynamics and Sufficiency in Estrogen Receptor–Regulated Transcription , 2000, Cell.

[163]  A. Quesada,et al.  Estrogen interacts with the IGF‐1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6‐hydroxdopamine lesions , 2004, Journal of neuroscience research.

[164]  P. Argos,et al.  Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A , 1986, Nature.

[165]  C. Pike,et al.  Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer's disease. , 2001, Journal of neurochemistry.

[166]  G. Rune,et al.  Proliferation and apoptosis of hippocampal granule cells require local oestrogen synthesis , 2006, Journal of neurochemistry.

[167]  F. Sohrabji,et al.  Reproductive age modulates the impact of focal ischemia on the forebrain as well as the effects of estrogen treatment in female rats , 2010, Neurobiology of Aging.

[168]  M. Kindy,et al.  Differential modulation of estrogen receptors (ERs) in ischemic brain injury: a role for ERalpha in estradiol-mediated protection against delayed cell death. , 2006, Endocrinology.

[169]  S. Johann,et al.  Neuroprotection by gonadal steroid hormones in acute brain damage requires cooperation with astroglia and microglia , 2013, The Journal of Steroid Biochemistry and Molecular Biology.

[170]  I. Torres-Aleman,et al.  The many faces of insulin-like peptide signalling in the brain , 2012, Nature Reviews Neuroscience.

[171]  P. Ascenzi,et al.  17β‐Oestradiol Anti‐Inflammatory Effects in Primary Astrocytes Require Oestrogen Receptor β‐Mediated Neuroglobin Up‐Regulation , 2013, Journal of neuroendocrinology.

[172]  T. Wieloch,et al.  Impact of estrogen receptor beta activation on functional recovery after experimental stroke , 2014, Behavioural Brain Research.

[173]  S. Hila,et al.  Regulation of cytokine-induced neuron death by ovarian hormones: involvement of antiapoptotic protein expression and c-JUN N-terminal kinase-mediated proapoptotic signaling. , 2004, Endocrinology.

[174]  D. Brann,et al.  Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia , 2015, The Journal of Steroid Biochemistry and Molecular Biology.

[175]  L. Remage-Healey,et al.  Sex-specific, rapid neuroestrogen fluctuations and neurophysiological actions in the songbird auditory forebrain. , 2012, Journal of neurophysiology.

[176]  L. Garcia-Segura,et al.  Selective estrogen receptor modulators protect hippocampal neurons from kainic acid excitotoxicity: differences with the effect of estradiol. , 2004, Journal of neurobiology.

[177]  Shiuan Chen,et al.  The HDAC inhibitor LBH589 (panobinostat) is an inhibitory modulator of aromatase gene expression , 2010, Proceedings of the National Academy of Sciences.

[178]  Rhonda R. Voskuhl,et al.  Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)α and ERβ ligand treatment , 2007, Proceedings of the National Academy of Sciences.

[179]  R. Brinton,et al.  17β-estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: A potential initiation mechanism for estrogen-induced neuroprotection , 2005, Neuroscience.

[180]  Yunfeng Wang,et al.  Morphine Protects against Intracellular Amyloid Toxicity by Inducing Estradiol Release and Upregulation of Hsp70 , 2011, The Journal of Neuroscience.

[181]  Intriguing Roles of Hippocampus-Synthesized 17β-Estradiol in the Modulation of Hippocampal Synaptic Plasticity , 2014, Journal of Molecular Neuroscience.

[182]  Quanguang Zhang,et al.  GPR30 mediates estrogen rapid signaling and neuroprotection , 2014, Molecular and Cellular Endocrinology.

[183]  L. Garcia-Segura,et al.  Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair , 1999, Neuroscience.