Skip to main content
SpringerLink
Log in

Estrogen-Mediated Neuroprotection: Hope to Combat Neuronal Degeneration and Synaptic Plasticity Post-menopause

  • Chapter
  • First Online:
Brain Aging and Therapeutic Interventions

  • 1052 Accesses

Abstract

Recent decade has seen a surge in identifying modifiable risk and protective factors for cognitive decline associated with natural aging and with common dementing disorders such as Alzheimer’s disease (AD). Ovarian steroid hormone estrogen is extensively studied among these factors with profound effects on many tissues and organs, including the brain. Brain aging in female is also accompanied with decline in estrogen levels. In women, it is characterized by natural depletion of hormone levels and menopause, whereas in rodents, it results in estropause. A decent amount of evidence associates the estrogen (E2, 17βestradiol) with hippocampal activity, an area of brain related to cognition and memory. Presence of estrogen receptors (ER) in the hippocampus gives further evidence to it being one of the target brain regions for the hormone activity. Our findings have revealed that ovariectomy or natural aging leads to decreased synaptic activity, degenerative cytoarchitectural changes and altered protein levels in hippocampal neurons. Further, it was seen that long-term estrogen therapy maintains the synaptic plasticity, regulates apoptotic proteins and affords neuroprotection to the hippocampal neurons through both the nuclear and membrane estrogen receptor mediated pCREB and MAPK activation. Interestingly, normal aging also exhibits immune activation and cell infiltration in the brain. Neuroprotective effects of estrogen may include its anti-inflammatory response via regulating the neuro-immune response and levels of pro-inflammatory cytokines. However, the exact mechanism of anti-inflammatory actions of estrogen in senescent female brain is not yet fully characterized and needs to be undertaken to fully embark on neuro-immune processes in female brain aging. Attention is now largely focused on collective and beneficial approach of estrogen replacement therapy that shall not only support the cognitive function but also prevent neurodegenerative pathologies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Baron-Cohen S, Knickmeyer RC, Belmonte MK (2005) Sex differences in the brain: implications for explaining autism. Science 310:819–823

    Article  PubMed  CAS  Google Scholar 

  • Bagetta G, Chiappetta O, Amantea D, Iannone M, Rotiroti D, Costa A, Nappi G, Corasaniti MT (2004) Estradiol reduces cytochrome c translocation and minimizes hippocampal damage caused bytransient global ischemia in rat. Neurosci Lett 368:87–91

    Article  PubMed  CAS  Google Scholar 

  • Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ (1999) Predictors of skeletal muscle mass in elderly men and women. Mech Aging Dev 107(2):123–136

    Article  PubMed  CAS  Google Scholar 

  • Behl C, Skutella T, Lezoualc’h F, Post A, Widmann M, Newton CJ, Holsboer F (1997) Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol 51(4):535–41

    PubMed  CAS  Google Scholar 

  • Behl C, Moosmann B, Manthey D, Heck S (2000) The female sex hormone oestrogen as neuroprotectant: activities at various levels. Novartis Found Symp 230:221–234

    Article  PubMed  CAS  Google Scholar 

  • Belcher SM, Zsarnovszky A (2001) Estrogenic actions in the brain: estrogen, phytoestrogens, and rapid intracellular signaling mechanisms. J Pharmacol Exp Ther 299(2):408–414

    PubMed  CAS  Google Scholar 

  • Belcredito S, Vegeto E, Brusadelli A, Ghisletti S, Mussi P, Ciana P, Maggi A (2001) Estrogen neuroprotection: the involvement of the Bcl-2 binding protein BNIP2. Brain Res Brain Res Rev 37(1–3):335–342

    Article  PubMed  CAS  Google Scholar 

  • Cahill L (2006) Why sex matters for neuroscience. Nat Rev Neurosci 7:477–484

    Article  PubMed  CAS  Google Scholar 

  • Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC (1999) Inflammatory cytokines IL-1a, IL-1b, IL-6, and TNF- a impart neuroprotection to an excitotoxin through distinct pathways1. J Immunol 163(7):3963–3968

    Google Scholar 

  • Ciriza I, Carrero P, Azcoitia I, Lundeen SG, Garcia-Segura LM (2004) Selective estrogen receptor modulators protect hippocampal neurons from kainic acid excitotoxicity: differences with the effect of estradiol. J Neurobiol 61:209–221

    Article  PubMed  CAS  Google Scholar 

  • Cantuti-Castelvetri I, Keller-McGandy C, Bouzou B, Asteris G, Clark TW, Frosch MP, and Standaert DG (2007) Effects of gender on nigral gene expression and parkinson disease. Neurobiol Dis 26:606–614

    Article  PubMed  CAS  Google Scholar 

  • Cosgrove KP, Mazure CM, and Staley JK (2007) Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry 62:847–855

    Article  PubMed  CAS  Google Scholar 

  • Couse JF, Korach KS (1999) Estrogen receptor null mice: what have we learned and where will they lead us. Endocr Rev 20(3):358–417

    Article  PubMed  CAS  Google Scholar 

  • Dewing P, Chiang CW, Sinchak K, Sim H, Fernagut PO, Kelly S, Chesselet MF, Micevych PE, Albrecht KH, Harley VR, et al. (2006) Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol 16:415–420

    Article  PubMed  CAS  Google Scholar 

  • Dubal DB, Kashon ML, Pettigrew LC, Ren JM, Finklestein SP, Rau SW, Wise PM (1998) Estradiol protects against ischemic injury. J Cereb Blood Flow Metab 18(11):1253–1258

    Article  PubMed  CAS  Google Scholar 

  • Fahlman MM, Boardley D, Flynn MG, Bouillon LE, Lambert CP, Braun WA (2000) Effects of hormone replacement therapy on selected indices of immune function in postmenopausal women. Gynecol Obstet Invest 50(3):189–193

    Article  PubMed  CAS  Google Scholar 

  • Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M (2000) Multiple actions of steroid hormones--a focus on rapid, nongenomic effects. Pharmacol Rev 52(4):513–556

    PubMed  CAS  Google Scholar 

  • Fillit H, Weinreb H, Cholst I, Luine V, McEwen B, Amador R, Zabriskie J (1986) Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer’s type. Psychoneuroendocrinology 11:337–345

    Article  PubMed  CAS  Google Scholar 

  • Gahring LC, Carlson NG, Kulmar RA, Rogers SW (1996) Neuronal expression of tumor necrosis factor a in the murine brain. Neuroimmunomodulation 3:289

    Article  PubMed  CAS  Google Scholar 

  • Giguère V, Yang N, Segui P, Evans RM (1988) Identification of a new class of steroid hormone receptors. Nature 331(6151):91–94

    Article  PubMed  Google Scholar 

  • Godbout JP, Johnson RW (2004) Interleukin-6 in the aging brain. J Neuroimmunol 147(1–2):141–144

    Article  PubMed  CAS  Google Scholar 

  • Gollapudi L, Oblinger MM (1999) Estrogen and NGF synergistically protect terminally differentiated, ERalpha-transfected PC12 cells from apoptosis. J Neurosci Res 1;56(5):471–481

    Article  PubMed  CAS  Google Scholar 

  • Green PS, Simpkins JW (2000) Neuroprotective effects of estrogens: potential mechanisms of action. Int J Dev Neurosci 18:347–358

    Article  PubMed  CAS  Google Scholar 

  • Gridley KE, Green PS, Simpkins JW (1997) Low concentrations of estradiol reduce beta-amyloid (25–35)-induced toxicity, lipid peroxidation and glucose utilization in human SK-N-SH neuroblastoma cells. Brain Res 778(1):158–165

    Google Scholar 

  • Gu Q, Moss RL (1996) 17 beta-Estradiol potentiates kainate-induced currents via activation of the cAMP cascade. J Neurosci 16(11):3620–3629

    PubMed  CAS  Google Scholar 

  • Halbreich U, Kahn LS (2000) Selective oestrogen receptor modulators--current and future brain and behaviour applications. Expert Opin Pharmacother 1:1385–1398

    Article  PubMed  CAS  Google Scholar 

  • Henderson VW (2008) Cognitive changes after menopause: influence of estrogen. Clin Obstet Gynecol 51(3):618–626

    Article  PubMed  Google Scholar 

  • Horsburgh K, Macrae IM, Carswell H (2002) Estrogen is neuroprotective via an apolipoprotein E-dependent mechanism in a mouse model of global ischemia. J Cereb Blood Flow Metab 22(10):1189–1195

    Article  PubMed  CAS  Google Scholar 

  • Jin K, Mao XO, Simon RP, Greenberg DA (2001) Cyclic AMP response element binding protein (CREB) and CREB binding protein (CBP) in global cerebral ischemia. J Mol Neurosci 16(1):49–56

    Google Scholar 

  • Kobayashi Y, Shinozawa T (1997) Effect of dibutyrylcAMP and several reagents on apoptosis in PC12 cells induced by a sialoglycopeptide from bovine brain. Brain Res 778(2):309–317

    Article  PubMed  CAS  Google Scholar 

  • Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 93(12):5925–5930

    Article  PubMed  CAS  Google Scholar 

  • Littleton-Kearney MT, Ostrowski NL, Cox DA, Rossberg MI, Hurn, PD (2002) Selective estrogen receptor modulators: tissue actions and potential for CNS protection. CNS Drug Rev 8:309–330

    Article  PubMed  CAS  Google Scholar 

  • Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995) The nuclear receptor superfamily: the second decade. Cell 83(6):835–839

    Article  PubMed  CAS  Google Scholar 

  • Matejuk A, Adlard K, Zamora A, Silverman M, Vandenbark AA, Offner H (2001) 17 beta-estradiol inhibits cytokine, chemokine, and chemokine receptor mRNA expression in the central nervous system of female mice with experimental autoimmune encephalomyelitis. J Neurosci Res 65(6):529–542

    Article  PubMed  CAS  Google Scholar 

  • Matsuda J, Vanier MT, Saito Y, Suzuki K, Suzuki K (2001)Dramatic phenotypic improvement during pregnancy in a genetic leukodystrophy: estrogen appears to be a critical factor. Hum Mol Genet 10(23):2709–2715

    Article  PubMed  CAS  Google Scholar 

  • McArthur S, McHale E, and Gillies GE (2007a) The size and distribution of midbrain dopaminergic populations are permanently altered by perinatal glucocorticoid exposure in a sex- region- and time-specific manner. Neuropsychopharmacology 32:1462–1476

    Article  CAS  Google Scholar 

  • McCarthy MM and Konkle AT (2005) When is a sex difference not a sex difference? Front Neuroendocrinol 26:85–102

    Article  PubMed  CAS  Google Scholar 

  • McEwen BS (2001) Estrogens effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol 91(6):2785–2801

    PubMed  CAS  Google Scholar 

  • Mehra RD, Sharma K, Nyakas C, Vij U (2005) Estrogen receptor alpha and beta immunoreactive neuron in normal adult and aged female rat hippocampus: a qualitative and qunatitative study. Brain Research 1056:22–35

    Article  PubMed  CAS  Google Scholar 

  • Mitchner NA, Garlick C, Ben-Jonathan N (1998) Cellular distribution and gene regulation of estrogen receptors alpha and beta in the rat pituitary gland. Endocrinology 139(9):3976–3983

    Article  PubMed  CAS  Google Scholar 

  • Moosmann B, Behl C (1999) The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Proc Natl Acad Sci U S A 96(16):8867–8872

    Article  PubMed  CAS  Google Scholar 

  • Morley JE (2001) Androgens and aging. Maturitas 38(1): 61–71

    Article  PubMed  CAS  Google Scholar 

  • Murphy DD, Segal M (1997) Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein. Proc Natl Acad Sci 94(4):1482–1487

    Google Scholar 

  • Neurgaren BL, Kraines RJ (1965) Menopausal symptoms in women of various ages. Psycho Med 27:266–273

    Google Scholar 

  • Osterlund M, Kuiper GG, Gustafsson JA, Hurd YL (1998) Differential distribution and regulation of estrogen receptor-alpha and -beta mRNA within the female rat brain. Brain Res Mol Brain Res 54(1):175–180

    Article  PubMed  CAS  Google Scholar 

  • Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS (1997) Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 277(5331):1508–1510

    Article  PubMed  CAS  Google Scholar 

  • Pan W, Zadina JE, Harlan RE, Weber JT, Banks WA, Kastin AJ (1998) Tumor necrosis factor-a: a neuromodulator. Endocrinology 139(9):3976–3983

    Article  Google Scholar 

  • Pike CJ (1999) Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer’s disease. J Neurochem 72(4):1552–1563

    Article  PubMed  CAS  Google Scholar 

  • Pike CJ, Rosario ER, Nguyen TV (2006) Androgens, aging, and Alzheimer’s disease. Endocrine 29(2): 233–241

    Article  PubMed  CAS  Google Scholar 

  • Porter VR, Greendale GA, Schocken M, Zhu X, Effros RB (2001) Immune effects of hormone replacement therapy in post-menopausal women. Exp Gerontol 36(2):311–326

    Article  PubMed  CAS  Google Scholar 

  • Rosario ER, Pike CJ (2008) Androgen regulation of beta-amyloid protein and the risk of Alzheimer’s disease. Brain Res Rev 57(2): 444–453

    Article  PubMed  CAS  Google Scholar 

  • Saucedo R, Rico G, Basurto L, Ochoa R, Zárate A (2002) Transdermal estradiol in menopausal women depresses interleukin-6 without affecting other markers of immune response. Gynecol Obstet Invest 53(2):114–117

    Article  PubMed  CAS  Google Scholar 

  • Segal M, Murphy DD (1998) CREB activation mediates plasticity in cultured hippocampal neurons. Neural Plast 6(3):1–7

    Article  PubMed  CAS  Google Scholar 

  • Sharma K, Mehra RD. (2008) Long-term administration of estrogen or tamoxifen to ovariectomized rats affords neuroprotection to hippocampal neurons by modulating the expression of Bcl-2 and Bax. Brain Res 1204:1–15

    Article  PubMed  CAS  Google Scholar 

  • Sharma K, Mehra RD, Dhar P, Vij U (2007) Chronic exposure to estrogen and tamoxifen regulates synaptophysin and phosphorylated cAMP response element-binding (CREB) protein expression in CA1 of ovariectomized rat hippocampus. Brain Res 1132(1):10–19

    Article  PubMed  CAS  Google Scholar 

  • Sherwin BB (1988) Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 13:345–357

    Article  PubMed  CAS  Google Scholar 

  • Sherwin BB (2000) Oestrogen and cognitive function throughout the female lifespan. Novartis Found. Symp 230:188–196

    CAS  Google Scholar 

  • Singer CA, Rogers KL, Dorsa DM (1998) Modulation of Bcl-2 expression: a potential component of estrogen protection in NT2 neurons. Neuroreport 9(11):2565–2568

    Article  PubMed  CAS  Google Scholar 

  • Singer CA, Figueroa-Masot XA, Batchelor RH, Dorsa DM (1999) The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons. J Neurosci 19(7):2455–2463

    PubMed  CAS  Google Scholar 

  • Swaab DF (2004) Sexual differentiation of the human brain: relevance for gender identity, transsexualism and sexual orientation. Gynecol Endocrinol 19:301–312

    Article  PubMed  CAS  Google Scholar 

  • Szegõ EM, Barabás K, Balog J, Szilágyi N, Korach KS, Juhász G, Abrahám IM (2006) Estrogen induces estrogen receptor alpha-dependent cAMP response element-binding protein phosphorylation via mitogen activated protein kinase pathway in basal forebrain cholinergic neurons in vivo. J Neurosci 26(15):4104–4110

    Article  PubMed  Google Scholar 

  • Tsai MJ, O’Malley BW (1994) Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 63:451–486

    Article  PubMed  CAS  Google Scholar 

  • Toulmond S, Parnet P, Linthorst AC (1996) When cytokines get on your nerves: cytokine networks and CNS pathologies. Trends Neurosci 19:409

    PubMed  CAS  Google Scholar 

  • Vegeto E, Belcredito S, Etteri S, Ghisletti S, Brusadelli A, Meda C, Krust A, Dupont S, Ciana P, Chambon P, Maggi A (2003) Estrogen receptor-alpha mediates the brain antiinflammatory activity of estradiol. Proc Natl Acad Sci U S A 100(16):9614–9619

    Article  PubMed  CAS  Google Scholar 

  • Wappler EA, Szilágyi G, Gál A, Skopál J, Nyakas C, Nagy Z, Felszeghy K (2009) Adopted cognitive tests for gerbils: Validation by studying aging and ischemia. Physiol Behav 97:107–114

    Article  PubMed  CAS  Google Scholar 

  • Wappler EA, Felszeghy K, Szilágyi G, Gál A, Skopál J, Mehra RD, Nyakas C, Nagy Z (2010) Neuroprotective effects of estrogen treatment on ischemia-induced behavioural deficits in ovariectomized gerbils at different ages. Behav Brain Res 209(1):42–48

    Article  PubMed  CAS  Google Scholar 

  • Wappler EA, Felszeghy K, Varshney M, Mehra RD, Nyakas C, Nagy Z (2011) Brain plasticity following ischemia: effect of estrogen and other cerebroprotective drugs. In: Balestrino M (ed) Brain ischemia: Book 2. InTech – Open Access Publisher, ISBN 979–953–307–734–4

    Google Scholar 

  • Watters JJ, Dorsa DM (1998) Transcriptional effects of estrogen on neuronal neurotensin gene expression involve cAMP/protein kinase A-dependent signaling mechanisms. J Neurosci 18(17):6672–6680

    PubMed  CAS  Google Scholar 

  • Weaver CE Jr, Park-Chung M, Gibbs TT, Farb DH (1997) 17beta-Estradiol protects against NMDA-induced excitotoxicity by direct inhibition of NMDA receptors. Brain Res 761(2):338–341

    Article  PubMed  CAS  Google Scholar 

  • Weissman BA, Daly JW, Skolnick P (1975) Diethylstilbestrol-elicited accumulation of cyclic AMP in incubated rat hypothalamus. Endocrinology 97(6):1559–1566

    Article  PubMed  CAS  Google Scholar 

  • Wilson CA and Davies DC (2007) The control of sexual differentiation of the reproductive system and brain. Reproduction 133:331–359

    Article  PubMed  CAS  Google Scholar 

  • Ye SM, Johnson RW (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9(4):183–192

    Article  PubMed  CAS  Google Scholar 

  • Zhou Y, Watters JJ, Dorsa DM (1996) Estrogen rapidly induces the phosphorylation of the cAMP response element binding protein in rat brain. Endocrinology 137(5):2163–2166

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anatomy, All India Institute of Medical Sciences, 110029, New Delhi, India

    Raj D. Mehra, Mukesh K. Varshney & Pavan Kumar

Authors
  1. Raj D. Mehra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mukesh K. Varshney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pavan Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raj D. Mehra .

Editor information

Editors and Affiliations

  1. , Department of Zoology, Banaras Hindu University, Varanasi, 221005, India

    Mahendra K. Thakur

  2. , Department of Molecular Biology, Aarhus University, Gustav Wieds Vej 10-C, Aarhus-C, 8000, Denmark

    Suresh I.S. Rattan

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Mehra, R.D., Varshney, M.K., Kumar, P. (2012). Estrogen-Mediated Neuroprotection: Hope to Combat Neuronal Degeneration and Synaptic Plasticity Post-menopause. In: Thakur, M., Rattan, S. (eds) Brain Aging and Therapeutic Interventions. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5237-5_14

Download citation

Publish with us

Policies and ethics

Search

Navigation