The actions of estradiol in the brain involve the interaction with growth factors, such as insulin-like growth factor-I (IGF-I). Many cells in the brain coexpress receptors for estradiol (ERs) and IGF-I (IGF-IR) and both factors interact to regulate neural function. Several studies have shown that there is an interaction of IGF-IR and ERs in neuroprotection. Neuroprotective effects of estradiol are blocked by the inhibition of IGF-IR signaling, while the neuroprotective effects of IGF-I are blocked by the inhibition of ER signaling. These findings suggest that the neuroprotective actions of estradiol and IGF-I after brain injury depend on the coactivation of both ERs and IGF-IR in neural cells. The relationship of ERα with IGF-IR through the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3β (PI3K/Akt/GSK3) signaling pathway may represent the point of convergence used by estradiol and IGF-I to cooperatively promote neuroprotection. Administration of estradiol to ovariectomized rats results in the association of ERα with IGF-IR and with components of the PI3K/Akt/GSK3 signaling pathway and in the regulation of the activity of Akt and GSK3 in the brain. Conversely, IGF-I regulates ERα transcriptional activity in neuroblastoma cells and the PI3K/Akt/GSK3 signaling pathway is involved in this effect.

Keywords:
Akt, β-Catenin, Estrogen receptors, Glycogen synthase kinase 3, Mitogen-activated protein kinase, Phosphatidylinositol 3-kinase, Tau
1.
Bondy CA, Cheng CM: Signaling by insulin-like growth factor 1 in brain. Eur J Pharmacol 2004;490:25–31.
2.
D’Ercole AJ, Ye P, Calikoglu AS, Gutierrez-Ospina G: The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol 1996;13:227–255.
3.
Garcia-Segura LM, Rodriguez JR, Torres-Aleman I: Localization of the insulin-like growth factor I receptor in the cerebellum and hypothalamus of adult rats: an electron microscopic study. J Neurocytol 1997;26:479–490.
4.
Cardona-Gomez GP, Mendez P, DonCarlos LL, Azcoitia I, Garcia-Segura LM: Interactions of estrogen and insulin-like growth factor-I in the brain: molecular mechanisms and functional implications. J Steroid Biochem Mol Biol 2002;83:211–217.
5.
Garcia-Ovejero D, Azcoitia I, DonCarlos LL, Melcangi RC, Garcia-Segura LM: Glia-neuron crosstalk in the neuroprotective mechanisms of sex steroid hormones. Brain Res Brain Res Rev 2005;48:273–286.
6.
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;388:507–525.
7.
Moss RL, Gu Q: Estrogen: mechanisms for a rapid action in CA1 hippocampal neurons. Steroids 1999;64:14–21.
8.
Raap DK, DonCarlos L, Garcia F, Muma NA, Wolf WA, Battaglia G, van de Kar LD: Estrogen desensitizes 5-HT1A receptors and reduces levels of Gz, Gi1 and Gi3 proteins in the hypothalamus. Neuropharmacology 2000;39:1823–1832.
9.
Bi R, Broutman G, Foy MR, Thompson RF, Baudry M: The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus. Proc Natl Acad Sci USA 2000;97:3602–3607.
10.
Cardona-Gomez GP, Mendez P, Garcia-Segura LM: Synergistic interaction of estradiol and insulin-like growth factor-I in the activation of PI3K/Akt signaling in the adult rat hypothalamus. Brain Res Mol Brain Res 2002;107:80–88.
11.
McEwen B: Estrogen actions throughout the brain. Recent Prog Horm Res 2002;57:357–384.
12.
Toran-Allerand CD, Singh M, Sétáló G: Novel mechanisms of estrogen action in the brain: new players in an old story. Front Neuroendocrinol 1999;20:97–121.
13.
Gu G, Rojo AA, Zee MC, Yu J, Simerly RB: Hormonal regulation of CREB phosphorylation in the anteroventral periventricular nucleus. J Neurosci 1996;16:3035–3044.
14.
Murphy DD, Segal M: Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein. Proc Natl Acad Sci USA 1997;94:1482–1487.
15.
Zhou Y, Watters JJ, Dorsa DM: Estrogen rapidly induces the phosphorylation of the cAMP response element binding protein in rat brain. Endocrinology 1996;137:2163–2166.
16.
Beyer C, Raab H: Nongenomic effects of oestrogen: embryonic mouse midbrain neurones respond with a rapid release of calcium from intracellular stores. Eur J Neurosci 1998;10:255–262.
17.
Carrer HF, Araque A, Buno A: Estradiol regulates the slow Ca2+-activated K+ current in hippocampal pyramidal neurons. J Neurosci 2003;23:6338–6344.
18.
Mermelstein PG, Becker JB, Surmeier DJ: Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor. J Neurosci 1996;16:595–604.
19.
Pozzo-Miller LD, Inoue T, Murphy DD: Estradiol increases spine density and NMDA-dependent Ca2+ transients in spines of CA1 pyramidal neurons from hippocampal slices. J Neurophysiol 1999;81:1404–1411.
20.
Cardona-Gomez GP, DonCarlos L, Garcia-Segura LM: Insulin-like growth factor I receptors and estrogen receptors colocalize in female rat brain. Neuroscience 2000;99:751–760.
21.
Garcia-Segura LM, Cardona-Gomez GP, Chowen JA, Azcoitia I: Insulin-like growth factor-I receptors and estrogen receptors interact in the promotion of neuronal survival and neuroprotection. J Neurocytol 2000;29:425–437.
22.
Garcia-Segura LM, Azcoitia I, DonCarlos LL: Neuroprotection by estradiol. Prog Neurobiol 2001;63:29–60.
23.
Torres-Aleman I: Role of insulin-like growth factors in neuronal plasticity and neuroprotection. Adv Exp Med Biol 2005;567:243–258.
24.
Azcoitia I, Sierra A, Garcia-Segura LM: Neuroprotective effects of estradiol in the adult rat hippocampus: interaction with insulin-like growth factor-I signalling. J Neurosci Res 1999;58:815–822.
25.
Quesada A, Micevych PE: Estrogen interacts with the IGF-1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6-hydroxdopamine lesions. J Neurosci Res 2004;75:107–116.
26.
D’Astous M, Mendez P, Morissette M, Garcia-Segura LM, Di Paolo T: 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. Mol Pharmacol 2006;69:1492–1498.
27.
Bi R, Foy MR, Vouimba RM, Thompson RF, Baudry M: Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway. Proc Natl Acad Sci USA 2001;98:13391–13395.
28.
Ivanova T, Mendez P, Garcia-Segura LM, Beyer C: Rapid stimulation of the PI3-kinase/Akt signalling pathway in developing midbrain neurones by oestrogen. J Neuroendocrinol 2002;14:73–79.
29.
Wilson ME, Liu Y, Wise PM: Estradiol enhances Akt activation in cortical explant cultures following neuronal injury. Brain Res Mol Brain Res 2002;102:48–54.
30.
Znamensky V, Akama KT, McEwen BS, Milner TA: Estrogen levels regulate the subcellular distribution of phosphorylated Akt in hippocampal CA1 dendrites. J Neurosci 2003;23:2340–2347.
31.
Guerra B, Diaz M, Alonso R, Marin R: Plasma membrane oestrogen receptor mediates neuroprotection against β-amyloid toxicity through activation of Raf-1/MEK/ERK cascade in septal-derived cholinergic SN56 cells. J Neurochem 2004;91:99–109.
32.
Kuroki Y, Fukushima K, Kanda Y, Mizuno K, Watanabe Y: Neuroprotection by estrogen via extracellular signal-regulated kinase against quinolinic acid-induced cell death in the rat hippocampus. Eur J Neurosci 2001;13:472–476.
33.
Singer CA, Figueroa-Masot XA, Batchelor RH, Dorsa DM: The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons. J Neurosci 1999;19:2455–2463.
34.
Honda K, Sawada H, Kihara T, Urushitani M, Nakamizo T, Akaile A, Shimohama S: Phosphatidylinositol 3-kinase mediates neuroprotection by estrogen in cultured cortical neurons, J Neurosci Res 2000;60:321–327.
35.
Yu X, Rajala RV, McGinnis JF, Li F, Anderson RE, Yan X, Li S, Elias RV, Knapp RR, Zhou X, Cao W: Involvement of insulin/phosphoinositide 3-kinase/Akt signal pathway in 17β-estradiol-mediated neuroprotection. J Biol Chem 2004;279:13086–13094.
36.
Zhang L, Rubinow DR, Xaing G, Li BS, Chang YH, Maric D, Barker JL, Ma W: Estrogen protects against β-amyloid-induced neurotoxicity in rat hippocampal neurons by activation of Akt. Neuroreport 2001;12:1919–1923.
37.
Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, Reusch JE: Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 2000;275:10761–10766.
38.
Kane LP, Shapiro VS, Stokoe D, Weiss A: Induction of NF-κB by the Akt/PKB kinase. Curr Biol 1999;9:601–604.
39.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857–868.
40.
Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM: Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 1999;398:630–634.
41.
Tang ED, Nunez G, Barr FG, Guan KL: Negative regulation of the Forkhead transcription factor FKHR by Akt. J Biol Chem 1999;274:16741–16746.
42.
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME: Akt phosphorylation of BAD couples survival signals to cell-intrinsic machinery. Cell 1997;91:231–241.
43.
Del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G: Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997;278:687–689.
44.
Cardona-Gomez GP, Mendez P, DonCarlos LL, Azcoitia I, Garcia-Segura LM: Interactions of estrogens and insulin-like growth factor-I in the brain: implications for neuroprotection. Brain Res Brain Res Rev 2001;37:320–334.
45.
Cardona-Gomez GP, Perez M, Avila J, Garcia-Segura LM, Wandosell F: Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3 and β-catenin, in the hippocampus. Mol Cell Neurosci 2004;25:363–373.
46.
Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA: Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995;378:785–789.
47.
Lovestone S, Reynolds CH, Latimer D, Davis DR, Anderton BH, Gallo JM, Hanger D, Mulot S, Marquardt B, Stabel S, Woodgett JR, Miller CCJ: Alzheimer’s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr Biol 1994;4:1077–1086.
48.
Blaustein JD: Minireview: Neuronal steroid hormone receptors: they’re not just for hormones anymore. Endocrinology 2004;145:1075–1081.
49.
Ma ZQ, Santagati S, Patrone C, Pollio G, Vegeto E, Maggi A: Insulin-like growth factors activate estrogen receptor to control the growth and differentiation of the human neuroblastoma cell line SK-ER3. Mol Endocrinol 1994;8:910–918.
50.
Patrone C, Gianazza E, Santagati S, Agrati P, Maggi A: Divergent pathways regulate ligand-independent activation of ERα in SK-N-BE neuroblastoma and COS-1 renal carcinoma cells. Mol Endocrinol 1998;12:835– 841.
51.
Ciana P, Raviscioni M, Mussi P, Vegeto E, Que I, Parker MG, Lowik C, Maggi A: In vivo imaging of transcriptionally active estrogen receptors. Nat Med 2002;9:82–86.
52.
Klotz DM, Hewitt SC, Ciana P, Raviscioni M, Lindzey JK, Foley J, Maggi A, DiAugustine RP, Korach KS: Requirement of estrogen receptor-α in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk. J Biol Chem 2002;277:8531–8537.
53.
Martin MB, Franke TF, Stoica GE, Chambon P, Katzenellenbogen BS, Stoica BA, McLemore MS, Olivo SE, Stoica A: A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. Endocrinology 2000;141:4503–4511.
54.
Font de Mora J, Brown M: AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Mol Cell Biol 2000;20:5041–5047.
55.
Mendez P, Garcia-Segura LM: Phosphatidyl inositol 3-kinase (PI3K) and glycogen synthase kinase 3 (GSK3) regulate estrogen receptor mediated transcription in neuronal cells. Endocrinology 2006;147:3027–3039.
56.
Mendez P, Azcoitia I, Garcia-Segura LM: Estrogen receptor-α forms estrogen-dependent multimolecular complexes with insulin-like growth factor receptor and phosphatidylinositol 3-kinase in the adult rat brain. Brain Res Mol Brain Res 2003;112:170–176.
57.
Benito M, Valverde AM, Lorenzo M: IGF-I: A mitogen also involved in differentiation processes in mammalian cells. Int J Biochem Cell Biol 1996;28:499–510.
58.
Kadowaki T, Tobe K, Honda-Yamamoto R, Tamemoto H, Kaburagi Y, Momomura K, Ueki K, Takahashi Y, Yamauchi T, Akanuma Y, Yazaki Y: Signal transduction mechanism of insulin and insulin-like growth factor-1. Endocr J 1996;43(suppl):S33–S41.
© 2006 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.