Hormones in Neurodegeneration, Neuroprotection, and Neurogenesis E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 777

Veröffentlichungsjahr: 2011

Beschreibung

As life expectancy increases and population ages, the already enormous impact of neurodegeneration on society will become even larger without better prevention and treatment. Developing strategies to prevent degeneration of neurons and to promote a healthy nervous system is, thus, critical. The development of pharmacological agents that would increase production of new neurons was recently facilitated by the identification of the hormonal regulators of various steps of adult neurogenesis. The proposed book is writen by a group of top world experts involved in the study of the mechanisms of hormonal control of brain damage and repair. The effects of thyroid and steroid hormones (estrogens, androgens, progestins, gluco-mineralo-corticoids, various neurosteroids) or polypeptide hormones (CRF, urocortins, somatostastin, GH/IGF, leptin, prolactin, PACAP, erythropoetin) on neuronal survival and neurogenesis in various neurodegenerative conditions and in brain aging will be discussed in detail. The proposed book is unique because it gives a comprehensive account of the neuroprotective and neurogenic effects of steroid and polypeptide hormones. Furthermore, new pharmacological approaches for treatment of neurodegenerative conditions are presented, based on the neuroprotective and neurogenic properties of natural and synthetic hormones.

Leseprobe

Contents

List of Contributors

Forward

Part I Estrogens, Progestins, Allopregnanolone and Neuroprotection

1 Interactions of Estradiol and Insulin-like Growth Factor-I in Neuroprotection: Implications for Brain Aging and Neurodegeneration

1.1 Introduction: Hormones, Brain Aging, and Neurodegeneration

1.2 Estradiol, IGF-I, Brain Aging, and Neuroprotection

1.3 Molecular Interactions of Estrogen Receptors and IGF-I Receptor in the Brain

1.4 Regulation of IGF-I Receptor Signaling by Estradiol in the Brain

1.5 Regulation of Estrogen Receptor Transcriptional Activity by IGF-I in Neural Cells

1.6 Implications of the Cross Talk between Estrogen Receptors and IGF-I Receptors for Brain Aging, and Neurodegeneration

Acknowledgment

References

2 Structure-Nongenomic Neuroprotection Relationship of Estrogens and Estrogen-Derived Compounds

2.1 Introduction

2.2 In vitro Assessments of Structure-Neuroprotective Activity Relationships

2.3 In vivo Assessment of Structure-Neuroprotective Activity Relationships

2.4 In vitro Assessment of Structure-Cell Signaling Relationships

2.5 Summary

Acknowledgment

References

3 Progestins and Neuroprotection: Why the Choice of Progestin Matters

3.1 Introduction

3.2 The Biology of Progesterone

3.3 Membrane-Associated Progesterone Receptors

3.4 Progesterone-Induced Protection

3.5 Mechanisms Underlying Progesterone's Protective Effects

3.6 Medroxyprogesterone Acetate

Acknowledgment

References

4 Endogenous and Synthetic Neurosteroids in the Treatment of Niemann-Pick Type C Disease

4.1 Introduction

4.2 Niemann-Pick Type C Disease as a Model of Disrupted Neurosteroidogenesis

4.3 Steroidogenesis and Neurosteroidogenesis in NP-C

4.4 Treatment of NP-C Mice with Allopregnanolone

4.5 Mechanism of Allopregnanolone Action:<allcaps> GABA</allcaps>a Receptor

4.6 Mechanism of Allopregnanolone Action: Pregnane-X Receptor

4.7 Mechanism of Allopregnanolone Action: Reduction of Cellular Oxidative Stress

4.8 Conclusions - Mechanisms of Allopregnanolone Action in Treatment of NP-C and Other Neurodegenerative Diseases

Acknowledgment

References

Part II Glucocorticoids, Dehydroepiandrosterone, Neuroprotection and Neuropathy 61

5 Glucocorticoids, Developmental "Programming," and the Risk of Affective Dysfunction

5.1 Introduction to Programming

5.2 Birth Weight and Neuropsychiatric Disorders

5.3 Glucocorticoids and Fetal Development

5.4 Glucocorticoids: the Endocrine Programming Factor

5.5 Fetal Tissue Glucocorticoid Sensitivity

5.6 Stress and Glucocorticoids: Key Programmers of the Brain

5.7 CNS Programming Mechanisms

5.8 Glucocorticoid Programming in Humans

5.9 Future Perspectives and Therapeutic Opportunities

5.10 Overview

References

6 Regulation of Structural Plasticity and Neurogenesis during Stress and Diabetes; Protective Effects of Glucocorticoid Receptor Antagonists

6.1 The Stress Response

6.2 HPA Axis and Glucocorticoids

6.3 Glucocorticoid Actions

6.4 Feedback Regulation

6.5 Stress and Depression

6.6 Stress-Induced Viability Changes in the Hippocampus: Effect on Function, Volume, Cell Number, and Apoptosis

6.7 Effects of Stress on Dendritic Atrophy, Spine, and Synaptic Changes

6.8 Adult Hippocampal Neurogenesis

6.9 Effect of Stress on Adult Hippocampal Neurogenesis

6.10 Normalization of the Effects of Stress on the Hippocampus by Means of GR Blockade

6.11 Normalization of Hippocampal Alterations during Diabetes Mellitus Using the GR Antagonist Mifepristone

6.12 Concluding Remarks

Acknowledgment

Disclosure

References

7 Neuroactive Steroids and Peripheral Neuropathy

7.1 Introduction

7.2 Regulation of Neuroactive Steroid Responsiveness in Peripheral Nerves

7.3 Schwann Cell Responses to Neuroactive Steroids

7.4 Sexually Dimorphic Changes of Neuroactive Steroid Levels Induced by Pathology in Peripheral Nerves

7.5 Neuroactive Steroids as Protective Agents in PNS

7.6 Chemotherapy-Induced Peripheral Neuropathy

7.7 Concluding Remarks

Acknowledgment

References

8 Neuroprotective and Neurogenic Properties of Dehydroepiandrosterone and its Synthetic Analogs

8.1 Introduction

8.2 Neuroprtective and Neurogenic Effects of DHEA in Hippocampal Neurons

8.3 Neuroprotective Effects of DHEA in Nigrostriatal Dopaminergic Neurons

8.4 Neuroprotective Effects of DHEA in Autoimmune Neurodegenerative Processes

8.5 Neuroprotective Effects of DHEA against Brain Ischemia and Trauma

8.6 Signaling Pathways Involved in the Effects of DHEA on Neuronal Cell Fate

8.7 Therapeutic Perspectives of DHEA and its Synthetic Analogs in Neurodegenerative Diseases

References

9 Neurosteroids and Pain

9.1 Introduction

9.2 GeneralBackground on Neurosteroids

9.3 Overview on Pain

9.4 Involvement of Endogenous Neurosteroids in the Control of Pain

9.5 Conclusion

Acknowledgment

References

Part III Polypeptide Hormones and Neuroprotection

10 The Insulin/IGF-1 System in Neurodegeneration and Neurovascular Disease

10.1 Introduction

10.2 Insulin and Insulin Growth Factors

10.3 Local versus Systemic Actions

10.4 Insulin/IGF Signaling Pathway

10.5 The Insulin/IGF Axis in the Brain

10.6 Insulin/IGF and Neuroprotection

10.7 Alzheimer's Disease

10.8 Parkinson's Disease

10.9 Vascular Dementia

10.10 Neurovascular Degeneration

10.11 Conclusion

References

11 Leptin Neuroprotection in the Central Nervous System

11.1 Introduction

11.2 Mutation of Leptin or Leptin Receptors

11.3 Neurotrophic Role of Leptin

11.4 Leptin Neuroprotection against Disorders of the Central Nervous System

11.5 Significance

References

12 Somatostatin and Neuroprotection in Retina

12.1 Introduction

12.2 Somatostatin and Related Peptides

12.3 Somatostatin Receptors and Signaling

12.4 Somatostatin and its Receptors in Retina

12.5 Localization of Somatostatin Receptors in Retinal Neurons

12.6 Somatostatin Receptor Function in Retinal Circuitry

12.7 Neuroprotection by Somatostatin Analogs

12.8 Mechanisms of SRIF's Neuroprotection

12.9 Therapeutic Potential of Somatostatin Agents

12.10 Conclusions

Acknowledgment

Abbreviations

References

13 Neurotrophic Effects of PACAP in the Cerebellar Cortex

13.1 Expression of PACAP and its Receptors in the Developing Cerebellum

13.2 Effects of PACAP on Granule Cell Proliferation

13.3 Effects of PACAP on Granule Cell Migration

13.4 Effects of PACAP on Granule Cell Survival

13.5 Effects of PACAP on Granule Cell Differentiation

13.6 Functional Relevance

Acknowledgment

References

14 The Corticotropin-Releasing Hormone in Neuroprotection

14.1 Introduction

14.2 The CRH Family of Proteins and Molecular Signal Transduction

14.3 From the Physiology to the Pathophysiology of CRH

14.4 CRH and Neurodegenerative Conditions

14.5 Protective Activities of CRH

14.6 Lessons from the Heart

14.7 Outlook

References

15 Neuroprotective and Neurogenic Effects of Erythropoietin

15.1 Introduction

15.2 EPO in Models of Neonatal Hypoxic-Ischemic Brain Injury

15.3 EPO in Models of Ischemic Stroke in Adults

15.4 EPO in Models ofTraumatic Brain Injury and Spinal Cord Trauma

15.5 EPO in Experimental Autoimmune Encephalomyelitis

15.6 EPO in Models of Peripheral Neuropathy

15.7 Summary

References

Part IV Hormones and Neurogenesis

16 Thyroid Hormone Actions on Glioma Cells

16.1 Introduction

16.2 Origins of Glioma

16.3 Glioma Cell Biology

16.4 Thyroid Hormone Analogs, Transport, and Metabolism

16.5 Thyroid Hormones and Brain Development

16.6 Nongenomic Actions of Thyroid Hormones

16.7 Hypothyroidism Suppresses Growth of Glioma in Patients

16.8 Molecular Mechanisms of Hypothyroidism-Induced Clinical Suppression of Glioma Progression

16.9 Future Perspectives

References

17 Gonadal Hormones, Neurosteroids, and Clinical Progestins as Neurogenic Regenerative Agents: Therapeutic Implications

17.1 Introduction

17.2 Gonadal Hormones, Neurosteroids, and Neurogenesis

17.3 Neurosteroid Regulation of Adult Neurogenesis

17.4 Gonadal Steroids, Clinical Progestins, and Neurosteroids as Neuroregenerative Therapeutics: Challenges and Strategies

References

18 Gonadotropins and Progestogens: Obligatory Developmental Functions during Early Embryogenesis and their Role in Adult Neurogenesis, Neuroregeneration and Neurodegeneration

18.1 Introduction

18.2 Hormonal Regulation of Human Embryogenesis

18.3 Progesterone: an Essential Neurotrophic Hormone during All Phases of Life

18.4 Age-Related Loss of Progesterone: Implications in the Pathophysiology of Neurodegenerative Diseases

18.5 Conclusion

References

19 Human Neural Progenitor Cells: Mitotic and Neurogenic Effects of Growth Factors, Neurosteroids, and Excitatory Amino Acids

19.1 Introduction

19.2 Neural Stem/Progenitor Cells as a Model of Human Cortical Development

19.3 Mitotic and Neurogenic Effects of a Neurosteroid: Dehydroepiandrosterone (DHEA)

19.4 Glutamate Enhances Proliferation and Neurogenesis in hNPCs

19.5 Increased Neurogenic ''Radial Glial''-like Cells within Human Neurosphere Cultures

19.6 Conclusions

Acknowledgment

References

20 Corticosterone, Dehydroepiandrosterone, and Neurogenesis in the Adult Hippocampus

20.1 Background

20.2 Glucocorticoids and Neurogenesis in the Adult Hippocampus

20.3 Conclusion

Acknowledgment

References

Index

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The Editors

Prof. Dr. Achille G. GravanisDept. of PharmacologyUniv. of Crete Med. School71110 HeraklionGreece

Prof. Dr. Synthia H. MellonCtr. Reproductive SciencesUniversity of CaliforniaP.O. Box 0556San Francisco, CA 94143-0556USA

CoverThe cover photo depicts sympathetic neurons in culture, isolated from superior cervical ganglia (SCG) ofE17 mouse embryos (With kind permission from the Dept. of Pharmacology, School of Medicine, University of Crete).

Limit of Liability/Disclaimer of Warranty:While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty can be created or extended by sales representatives or written sales materials. The Advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

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All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

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Foreword

To the scientific keywords of this book, I certainly like to add ''ageing'' and ''hope.'' Clearly, the main risk of neurodegeneration is increased lifespan, which characterizes the current evolution of mankind and, at the same time, today we have hope and even some remedies for improved understanding and means of maintaining active brain function until we die.

The CNS receives, modulates, and transfers to the body information from the environment; it controls our mental and affective life and is therefore largely in command of our behavior and activities. The hormonal system (which includes more than 50 distinct important molecules) is the main vector of the CNS, which gives orders to the rest of the body. Conversely, many hormones synthesized at the ''periphery'' have access to the brain and can modify its (re)actions. Hormones interact between them at levels of regulated synthesis, metabolism and activities. Age-dependent changes in secretion, distribution, receptors, and metabolism of hormones are important to study; they may be responsible for opposite effects according to the ''age.'' If the core of the receptors' structure is the same in most target cells, the receptor-associated proteins vary according to the tissue, physiological state, and so on, including the age of the person.

The CNS is certainly the most complex system of our body. With reference to hormones, not only does it control many glandular productions and therefore their activities, but it itself also synthesizes some of them already produced by peripheral glands, such as in the case of neurosteroids. For example [1], progesterone, made in Schwann cells and oligodendrocytes, is obviously the same as the progesterone coming from ovaries; it is, however, understandable that it works preferentially (probably or even uniquely) in the neighboring nerves and myelin, we even know that ''classical'' glandular progesterone may have the same activities. Does this double origin influence an important secondary sex characteristic explaining the pathological differences between men and women? Up to now, we believe that ''neuroprogesterone'' does not act through receptors different from those found at the periphery (nuclear receptors).

Among neurosteroids (synthesized in the CNS by definition) [2], pregnenolone is globally the most abundant, and it itself displays activities in the CNS, which have not yet been demonstrated elsewhere in the organism. MAP2, an important microtubule-associated protein abundant in the brain, is a pregnenolone receptor, binding the steroid specifically, thus stimulating tubulin polymerization [3]. Its derivative ''MAP4343,'' which is not metabolized to progesterone, is active to treat spinal cord injuries (European patent EP15831538, 2008). In addition, pregnenolone, when sulfated at the 3-position, becomes a ligand of the<allcaps> GABA</allcaps>a receptor, antagonist to allopregnanolone, and also an active ligand of an NMDA receptor [4].

The steroid receptors bind reversibly to the heat shock protein HSP90, and while working on the hetero-oligomeric forms of these receptors, an immunophilin (binding immunosuppressants) protein FKBP52 was discovered. This protein, abundant in the brain, is able to bind to Tau (a microtubule-associated protein) and display an ''anti Tau effect'' on Tau activity on tubulin polymerization [5]. These results deriving from hormonal studies (even without direct action o steroids) have led to unveil novel mechanisms applicable to neurodegenerative diseases (whether hormones will or will not additionally interfere has not been detected so far).

The previously cited examples make logical that this book includes a remarkable variety of functions for hormones acting, from and/or for, on the CNS. An incomplete list includes the interesting actions of estrogens; progesterone (and progestins); androgens themselves or in association with peptides of the insulin-growth hormone - IGF family; the role of leptin; the subtle and varied effects of glucocorticosteroids and dehydroepiandrosterone; and the effects of somatostatin, CRH, PACAP, and erythropoietin. No doubt therapeutic issues may arise from these studies. Hormonal activities can be manipulated at the level of production (an example with etifoxine stimulating the neurosteroid preg- nenolone production) [6], at the level of receptors (hormone antagonists), and at the level of their metabolism (via transport protein function and hepatic and renal functions).

I take the liberty to advise the readers of the book to keep it near their desk: they will have the privilege to conveniently obtain information on ''new neuroendocrinology'' as well as on appropriate references of talented authors of the reports.

Kremlin-Bicêtre, November 2010 Etienne Emile Baulieu

References

1. Koenig, H.L., Schumacher, M., Ferzaz, B., Do Thi, A.N., Ressouches, A., Guennoun, R., Jung-Testas, I., Robel, P., Akwa, Y., and Baulieu, E.E. (1995) Progesterone synthesis and myelin formation by Schwann cells. Science268,1500-1503.

2. Baulieu, E.E. (1997) in Recent Progress in Hormone Research vol. 52 (ed. P.M. Conn), The Endocrine Society Press, Bethesda, pp. 1-32.

3. Fontaine-Lenoir V., Chambraud B., Fellous A., David S., Duchossoy Y., Baulieu E.E., and Robel P. (2006) Microtubule-associated protein 2 (MAP2) is a neurosteroid receptor. Proc. Natl. Acad. Sci. USA,103, 4711-4716.

4. Baulieu, E.E., Robel, P., and Schumacher, M. (eds) (1999) Neuros- teroids. A new regulatory function in the nervous system. Humana Press, Totowa, New Jersey.

5. Chambraud B., Sardin E., Giustiniani J., Dounane O., Schumacher M., Goedert M., and Baulieu E.E. (2010) A role for FKBP52 in Tau protein function. Proc. Natl. Acad. Sci. USA.,107, 2658-2663.

6. Girard C., Liu S., Cadepond F., Adams D., Lacroix C., Verleye M., Gillardin J.M., Baulieu E.E., Schumacher M., and Schweizer-Groyer G. (2008) Etifoxine improves peripheral nerve regeneration and functional recovery. Proc. Natl. Acad. Sci. USA,105,20505-20510.

List of Contributors

María-Angéles Arevalo

Instituto Cajal

Consejo Superior de

Investigaciones Cientfficas

(C.S.I.C.)

Avenida Doctor Arce 37

28002 Madrid

Spain

Craig S. Atwood

Department of Medicine

University of Wisconsin-Madison

School of Medicine and Public

Health and Geriatric Research

Education and Clinical Center

Veterans administration Hospital

2500 Overlook Terrace

Madison, WI 53705

USA

and

Case Western Reserve University

Department of Pathology

2103 Cornell Road Cleveland, OH 44106

USA

and

School of Exercise

Biomedical and Health Sciences

Edith Cowan University

270 Joondalup Drive

Joondalup, 6027 WA

Australia

Iñigo Azcoitia

Universidad Complutense

Departamento de Biologia Celular

Facultad de Biologia

Jose Antonio Novais 2

28040 Madrid

Spain

Etienne Emile Baulieu

INSERM UMR 788

80 rue du Général Leclerc

94276 Kremlin-Bicetre

France

Christian Behl

University Medical Center of the

Johannes Gutenberg University

Mainz

Institute for Pathobiochemistry

55099 Mainz

Germany

Roberta Diaz Brinton

University of Southern California

School of Pharmacy

Department of Pharmacology and

Pharmaceutical Sciences

Los Angeles, CA 90033

USA

Donatella Caruso

University of Milan

Department of Pharmacological

Sciences

Via Balzaretti 9

20133 Milano

Italy

loannis Charalampopoulos

University of Crete

Department of Pharmacology

School of Medicine

Stavrakia

71110 Heraklion

Greece

Jun Chen

University of Pittsburgh

Department of Neurology and

Center of Cerebrovascular

Disease Research

3550 Terrace St.

Pittsburgh

PA15213

USA

Angela Clement

University Medical Center of the

Johannes Gutenberg University

Mainz

Institute for Pathobiochemistry

55099 Mainz

Germany

Douglas Covey

Washington University School of

Medicine

Department of Developmental

Biology

St. Louis, MO

USA

Faith B. Davis

Ordway Research Institute

Signal Transduction Laboratory

Albany, NY 12208

USA

Paul J. Davis

Ordway Research Institute

Signal Transduction Laboratory

Albany, NY 12208

USA

Anthony Falluel-Morel

University of Rouen

INSERM U982

Place E. Blondel

76821 Mont-Saint-Aignan

France

and

European Institute for Peptide

Research (IFRMP 23)

Place E. Blondel

76821 Mont-Saint-Aignan

France

and

International Laboratory

Samuel de Champlain

76821 Mont-Saint-Aignan

France

Carlos P. Fitzsimons

University of Amsterdam

Centre for Neuroscience

Swammerdam Institute of Life

Sciences, Amsterdam Science Park 904, 1098 XH

The Netherlands

and

Leiden University Division of

Medical Pharmacology

Leiden Amsterdam Center for

Drug Research

Einsteinweg 55

2300RA Leiden

The Netherlands

Ludovic Galas

European Institute for Peptide

Research (IFRMP 23)

Place E. Blondel

76821 Mont-Saint-Aignan

France

and

International Laboratory

Samuel de Champlain

76821 Mont-Saint-Aignan

France

and

Regional Platform for Cell

Imaging (PRIMACEN)

IFRMP 23

76821 Mont-Saint-Aignan

France

Luis M. Garcia-Segura

Instituto Cajal

Consejo Superior de

Investigaciones Cientfficas

(C.S.I.C.)

Avenida Doctor Arce 37

28002 Madrid

Spain

Silvia Giatti

University of Milan

Department of Endocrinology

Pathophysiology and applied

Biology

Via Balzaretti 9

20133 Milano

Italy

Wenhui Gong

University of California

Department of Obstetrics

Gynecology, and Reproductive

Sciences, The Center for

Reproductive Sciences

513 Parnassus Avenue

San Francisco, CA 94143

USA

Dariusz C. Gorecki

University of Portsmouth

School of Pharmacy and

Biomedical Sciences

St. Michael Boulevard

Portsmouth PO1 2DT

UK

Achille Gravanis

University of Crete

Department of Pharmacology

School of Medicine

Stavrakia

71110 Heraklion

Greece

Joe Herbert

University of Cambridge Cambridge

Centre for Brain

Repair

Forvie Site, Robinson Way

Cambridge CB20PY

UK

PuHu

University of Amsterdam

Centre for Neuroscience

Swammerdam Institute of Life

Sciences

Science Park 904

1098 XH Amsterdam

The Netherlands

and

University of Science and

Technology of China

Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology and Biophysics

Hefei, Anhui

PR China

Ahmet Höke

Johns Hopkins University School of Medicine

Department of Neurology and Neuroscience

Pathology Building Room 509

600 N. Wolfe Street

Baltimore, MD 21287

USA

Marian Joëls

University of Amsterdam

Centre for Neuroscience

Swammerdam Institute of Life Sciences

Science Park 904

1098 XH Amsterdam

The Netherlands

and

University Medical Center Utrecht

Department Neuroscience and Pharmacology

The Netherlands

Cherkaouia Kibaly

Université de Strasbourg

Equipe Stéroïides

Neuromodulateurs et

Neuropathologies

Unité de Physiopathologie et

Médecine Translationnelle

Faculté de Médecine

11 rue Humann

67000 Strasbourg

France

Harold K. Kimelberg

Ordway Research Institute

Signal Transduction Laboratory

Albany, NY 12208

USA

Narisorn Kitiyanant

Mahidol University

Institute of Molecular Biosciences

Phutthamonthon 4 Rd

Nakhonpathom 73170

Thailand

Edo Ronald de Kloet

Leiden University

Division of Medical Pharmacology

Leiden Amsterdam Center for Drug Research

Einsteinweg 55

2300RA Leiden

The Netherlands

Hitoshi Komuro

The Cleveland Clinic Foundation

Lerner Research Institute

Department of Neurosciences

Cleveland, Ohio 44195

USA

lakovos Lazaridis

University of Crete

Department of Pharmacology

School of Medicine

Stavrakia

71110 Heraklion

Greece

Helmar C. Lehmann

Heinrich Heine University Düsseldorf

Department of Neurology

Moorenstrasse 5

40225 Düsseldorf

Germany

Lifei Liu

University of Southern California

School of Pharmacy

Department of Pharmacology and Pharmaceutical Sciences

Los Angeles, CA 90033

USA

Paul J. Lucassen

University of Amsterdam

Centre for Neuroscience

Swammerdam Institute of Life Sciences, Science Park 904

1098 XH Amsterdam

The Netherlands

Jacalyn McHugh

The Cedars-Sinai Regenerative

Medicine Institute

8700 Beverly Blvd.

Los Angeles, CA 90048

USA

Sivan Vadakkadath Meethal

University of Wisconsin-Madison

Department of Neurological Surgery

School of Medicine and Public Health

600 Highland Avenue

Madison, WI 53792

USA

Roberto C. Melcangi

University of Milan

Department of Endocrinology

Pathophysiology and applied Biology

Via Balzaretti 9

20133 Milano

Italy

Synthia H. Mellon

University of California

Department of Obstetrics

Gynecology, and Reproductive

Sciences, The Center for Reproductive Sciences

513 Parnassus Avenue

San Francisco, CA 94143

USA

Ayikoe G. Mensah-Nyagan

Université de Strasbourg

Equipe Stéroïdes

Neuromodulateurs et

Neuropathologies

Unité de Physiopathologie et

Médecine Translationnelle

Faculté de Médecine

11 rue Humann

67000 Strasbourg

France

Laurence Meyer

Université de Strasbourg

Equipe Stéroïdes

Neuromodulateurs et

Neuropathologies

Unité de Physiopathologie et

Médecine Translationnelle

Faculté de Médecine

11 rue Humann

67000 Strasbourg

France

Bayanne Olabi

The Queen's Medical Research Institute, Endocrinology Unit

Centre for Cardiovascular Science

47 Little France Crescent

Edinburgh EH16 4TJ

UK

Charlotte Oomen

University of Amsterdam

Centre for Neuroscience

Swammerdam Institute of Life Sciences

Science Park 904, 1098 XF

Amsterdam

The Netherlands

Christine Patte-Mensah

Université de Strasbourg

Equipe Stéroïdes

Neuromodulateurs et

Neuropathologies

Unité de Physiopathologie et

Médecine Translationnelle

Faculté de Médecine

11 rue Humann

67000 Strasbourg

France

Evelyn Perez

Laboratory of Experimental Gerontology

Neurocognitive Aging Section

National Institute on Aging

Baltimore, MD

USA

Marzia Pesaresi

University of Milan

Department of Endocrinology

Pathophysiology and applied Biology

Via Balzaretti 9 20133 Milano

Italy

Scarlet Bella Pinnock

University of Cambridge

Cambridge Centre for Brain Repair

Forvie Site, Robinson Way

Cambridge CB2 OPY

UK

Yanina Revsin

Leiden University

Division of Medical Pharmacology

Leiden Amsterdam Center for Drug Research

Einsteinweg 55

2300RA Leiden

The Netherlands

Przemyslaw (Mike) Sapieha

Harvard Medical School

Department of Ophthalmology

300 Longwood Avenue Boston, MA

USA

and

University of Montreal

Faculty of Medicine

5415 Assomption Boulevard Montreal, Quebec

Canada

Véronique Schaeffer

Université de Strasbourg

Equipe Stéroïdes

Neuromodulateurs et

Neuropathologies

Unité de Physiopathologie et

Médecine Translationnelle

Faculté de Médecine

11 rue Humann

67000 Strasbourg

France

Marcus D. Schonemann

University of California

Department of Obstetrics

Gynecology and Reproductive Sciences, The Center for Reproductive Sciences

513 Parnassus Avenue

San Francisco, CA 94143

USA

Jonathan Seckl

The Queen's Medical Research Institute, Endocrinology Unit

Centre for Cardiovascular Science

47 Little France Crescent

Edinburgh EH16 4TJ

UK

Armando P. Signore

University of Pittsburgh

Department of Neurology and

Center of Cerebrovascular

Disease Research

3550 Terrace St.

Pittsburgh

PA15213

USA

James W. Simpkins

University of North Texas Health

Science Center, Department of

Pharmacology & Neuroscience

Institute for Aging and

Alzheimer's Disease Research

Fort Worth, TX USA

Meharvan Singh

University of North Texas Health

Science Center, Department of

Pharmacology & Neuroscience

Institute for Aging and Alzheimer's

Disease Research

Center FOR HER

3500 Camp Bowie Blvd.

Fort Worth, TX, 76107

USA

Lois Smith

Harvard Medical School

Department of Ophthalmology

300 Longwood Avenue Boston, MA

USA

Masatoshi Suzuki

University of Wisconsin Madison

Department of Comparative Biosciences

School of Veterinary Medicine

2015 Linden Dr. Madison

WI 53706

USA

Marc J. Tetel

Wellesley College

Neuroscience Program

106 Central St. Wellesley, MA 02481

USA

Kyriaki Thermos

University of Crete

Department of Pharmacology

School of Medicine

71110 Heraklion

Greece

David Vaudry

University of Rouen

INSERM U982

Place E. Blondel

76821 Mont-Saint-Aignan

France

and

European Institute for Peptide

Research (IFRMP 23)

Place E. Blondel

76821 Mont-Saint-Aignan

France

and

International Laboratory

Samuel de Champlain

76821 Mont-Saint-Aignan

France

and

Regional Platform for Cell

Imaging (PRIMACEN)

IFRMP23

76821 Mont-Saint-Aignan

France

Hubert Vaudry

University of Rouen

INSERM U982

Place E. Blandel

76821 Mont-Saint-Aignan

France

and

European Institute for Peptide

Research (IFRMP 23)

Place E. Blondel

76821 Mont-Saint-Aignan

France

and

International Laboratory

Samuel de Champlain

76821 Mont-Saint-Aignan

France

and

Regional Platform for Cell

Imaging (PRIMACEN)

IFRMP 23

76821 Mont-Saint-Aignan

France

Erno Vreugdenhil

Leiden University, Division of Medical Pharmacology

Leiden Amsterdam Center for Drug Research

Einsteinweg 55

2300RA Leiden

The Netherlands

Suping Wang

University of Pittsburgh

Department of Neurology and Center of Cerebrovascular

Disease Research

3550 Terrace St.

Pittsburgh, PA 15213

USA

Zhongfang Weng

University of Pittsburgh

Department of Neurology and Center of Cerebrovascular

Disease Research

3550 Terrace St.

Pittsburgh, PA 15213

USA

Kun Don Yi

University of North Texas Health

Science Center, Department of Pharmacology and Neuroscience,

Institute for Aging and Alzheimer's Disease Research

Fort Worth, TX

USA

Feng Zhang

University of Pittsburgh

Department of Neurology and Center of Cerebrovascular

Disease Research

3550 Terrace St.

Pittsburgh, PA 15213

USA

Min Zhou

Ordway Research Institute

Signal Transduction Laboratory

Albany, NY 12208

USA

Part I

Estrogens, Progestins, Allopregnanolone and Neuroprotection

1

Interactions of Estradiol and Insulin-like Growth Factor-I in Neuroprotection: Implications for Brain Aging and Neurodegeneration

María-Angeles Arévalo, Luis M. Garcia-Segura, and Iñigo Azcoitia

Estradiol and insulin-like growth factor-I (IGF-I) interact in the nervous system to promote neuroprotection. This interaction is mediated by multiple intracellular signaling mechanisms in which several molecules such as estrogen receptor (ER) α, phosphatidylinositol 3-kinase (PI3K), glycogen synthase kinase 3β (GSK3β), and β-catenin play a central role. Decreased hormonal levels in plasma with aging and changes in the synthesis of the ligands, and the expression of the receptors in the brain under neurodegenerative conditions may alter the neuroprotective interactions of estradiol and IGF-I.

1.1Introduction: Hormones, Brain Aging, and Neurodegeneration

The aging process affects all tissues and organs, including the brain. Individual variations in decline of cognitive skills, development of affective disorders, and neurodegenerative diseases with aging suggest that brain deterioration is not only the result of age per sebut probably also represents a failure to adapt to age-associated homeostatic changes [1]. Hormones are involved somewhat in the aging process since, with aging, the levels of many of them change in the plasma. Several hormones such as the growth hormone, IGF-I, dehydroepiandrosterone, and sex hormones decrease with aging in mammals [1]. In humans, their change is associated in time with the progression of neurodegenerative disorders, increased depressive symptoms, and other psychological disturbances [1]. This suggests that the modification in hormone levels, due to aging, may have a negative impact on brain function. Alternatively, since the brain is an important center for endocrine control, brain aging may be involved in the hormonal changes. These hormonal changes may, in part, represent a positive adaptive response to the aging process [1].

Even if the hormonal changes are a general positive adaptation to aging, they may have a negative impact on the brain. The decrease in the levels of neuroprotective hormones in older people may result in reduced protection against the environmental and genetic factors that promote neurodegeneration. However, not all hormones exert neuroprotective effects. Thereisconsiderableevidenceto show a link between stress, hypothalamo-pituitary-adrenal (HPA) axis dysfunction, memory disorders, and aging [2]. The hippocampus is vulnerable to both stress and aging. Stress and glucocorticoids alter hippocampal neurogenesis [3] and may lead to hippocampal damage. Not only may stress in adulthood increase brain damage and brain aging, but also stress during brain development may result in permanent brain abnormalities in adult life. Prenatal stress increases anxiety-like behavior and induces dysfunction of the negative feedback of the HPA axis [4]. With aging, rats subjected to prenatal stress exhibited hyperactivity of the HPA axis associated with spatial learning impairments [5, 6].

1.2Estradiol, IGF-I, Brain Aging, and Neuroprotection

Some hormones, such as estradiol and IGF-I, may antagonize the damaging effects of adrenal steroids. IGF-I attenuates spatial learning deficits in aged rats and promotes neurogenesis in the hippocampus [6]. Chronic IGF-I infusion in the brain restores the spatial learning abilities of aged rats that were stressed during prenatal life. IGF-I also up-regulates neurogenesis in the hippocampus of these animals and reduces their HPA axis dysfunction [6]. Interestingly, IGF-I increases estradiol levels in the plasma of aged rats that are submitted to prenatal stress [6]. Estradiol, in turn, stimulates neurogenesis in the hippocampus of young and old rats and prevents hippocampal damage induced by excitotoxic injuries [1]. In addition, the signaling of estradiol and IGF-I interacts to promote neuroprotection [7]. Consequently, low levels of protective hormones, such as IGF-I and estradiol, in older individuals may increase the risk of neural damage induced by stress hormones or by previous stressful experiences. To understand how these hormones affect the aging process in the brain and to develop adequate protocols for possible hormone therapies to prevent brain deterioration, we need to know their neuroprotective mechanisms and how these are modulated in the aged brain.

IGF-I and estradiol prevent neuronal cell death in different experimental models of neurodegenerative diseases. The interaction of IGF-I and estradiol in neuroprotection has been assessed in ovariectomized rats in vivo, using systemic administration of kainic acid to induce degeneration of hippocampal hilar neurons [8], an experimental model of excitotoxic cell death. Both the systemic administration of estradiol and the intracerebroventricular infusion of IGF-I prevent hilar neuronal loss induced by kainic acid. The neuroprotective effect of estradiol is blocked by the intracerebroventricular infusionofanIGF-I receptor antagonist, while the neuroprotective effect of IGF-I is blocked by the intracerebroventricular infusion of the ER antagonist ICI 182, 780 [8]. Similar results have been obtained in ovariectomized rats after the unilateral infusion of 6-hydroxydopamine into the medial forebrain bundle to injure the nigrostriatal dopaminergic pathway [9], a model of Parkinson’s disease. Pretreatment with estradiol or IGF-I significantly prevents the loss of substantia nigra compacta neurons and the related motor disturbances. Blockage of IGF-I receptor by the intracerebroventricular administration of an IGF-I receptor antagonist attenuates the neuroprotective effects of both estrogen and IGF-I [9]. Furthermore, the neuroprotective action of estradiol against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in the nigrostriatal system of male mice is associated with the regulation of IGF-I receptor signaling [10]. These findings suggest that the neuroprotective actions of estradiol and IGF-I after brain injury depend on the coactivation of both ERs and IGF-I receptor in neural cells.

1.3Molecular Interactions of Estrogen Receptors and IGF-I Receptor in the Brain

The interaction of the neuroprotective actions of estradiol and IGF-I may be the consequence of an interaction of ERα and the IGF-I receptor in a macromolecular complex associated with components of the PI3K signaling pathway [11]. Immunohistochemical analyses have shown that ERs and IGF-I receptor colocalize in different neuronal and glial populations in the rat central nervous system in vivo[12, 13]. In addition, immunoprecipitation studies have shown that estradiol administration to adult ovariectomized rats results in a transient increase in the association between IGF-I receptor and ERα in the brain [14]. The interaction is coincident in time with the increase in tyrosine phosphorylation of IGF-I receptor, suggesting a possible causal relationship. Estradiol also increases the interaction between p85 and insulin receptor substrate (IRS)-1 [14], one of the first events in the signal transduction of the IGF-I receptor, further suggesting that the increase in IGF-I receptor phosphorylation induced by estradiol reflects functional activation of this receptor. In addition, ERα interacts with other components of the IGF-I receptor signaling pathway, such as the p85 subunit of the PI3K [14]. This interaction is present in control ovariectomized animals and increases after estradiol treatment. A similar estradiol-induced association of ERα and p85 occurs in the mammary cancer cell line MCF-7 [15] and in human vascular endothelial cells [16]. Interestingly, the interaction between ERα and the IGF-I receptor is also increased by the intracerebroventricular administration of IGF-I [14]. These findings suggest that the interaction of ERα with the IGF-I receptor is part of the mechanisms involved in the signaling of both IGF-I and estradiol in the brain.

1.4Regulation of IGF-I Receptor Signaling by Estradiol in the Brain

Invitroand invivostudies have shown that, in the brain, estradiol may rapidly activate the PI3K and the mitogen-activated protein kinase (MAPK) signaling pathways. These are the two main signal transduction cascades coupled to the IGF-I receptor. Estradiol also induces the phosphorylation of Akt, one of the main effectors of the PI3K pathway in the brain [7, 17–20]. Both MAPK activation and PI3K/Akt activation are involved in the neuroprotective effects of estradiol in different experimental models of neurodegeneration [21–27]. Akt activation may mediate the effects of estradiol on the activity and expression of antiapoptotic molecules, such as Bcl-2 [10, 28]. The activation of Akt by estradiol also has implications for neuroprotection via the modulation of GSK3β activity [29]. Under pathological conditions, GSK3β may be responsible for the hyperphosphorylation of Tau in Alzheimer’s disease [30] and its inhibition is associated with the activation of survival pathways in neurons [31]. Interestingly, estradiol increases the amount of inactive GSK3β (ser-9 phosphorylated) and decreases the phosphorylation of Tau in the hippocampus [29]. In addition, the inhibition of GSK3β by estradiol in neuroblastoma cells and in primary cortical neurons is associated with the stabilization of β-catenin and its translocation to the cell nucleus, where it acts as a cotranscriptional modulator using canonical T cell factor (TCF)/lymphoid enhancer binding factor-1 (LEF-1)-mediated transcription, in a manner similar to that produced by Wnt3a [32].

1.5Regulation of Estrogen Receptor Transcriptional Activity by IGF-I in Neural Cells

In addition to classical activation of ER by estradiol binding, ER transcriptional activity can be regulated by ligand-independent mechanisms. Intracellular kinase signaling pathways, activated by extracellular growth or trophic factors, regulate the ability of ERs to promote changes in gene expression. IGF-I is one of the extracellular regulators of these kinase pathways that have been shown to promote ER-dependent transcription. In different cell lines, including neuroblastoma cells, IGF-I may activate ERs in the absence of estradiol and regulate ER-mediated gene expression [33–37]. In neuroblastoma cells, IGF-I may have a different regulation of the activity of ERα depending on whether the ER ligand is present or not. In the absence of estradiol, IGF-I increases ERα activity by using the Ras/MAPK signaling pathway [34]. In contrast, IGF-I negatively regulates ERα transcriptional activity in the presence of estradiol. This effect of IGF-I is mediated by the PI3K/Akt/GSK3β pathway, which induces the translocation of β-catenin to the cell nucleus. In turn, β-catenin binds to ERα in the nucleus and inhibits its transcriptional activity [38]. Thus, by using different components of its signaling system, IGF-I may regulate ligand-independent and -dependent ER transcriptional activity in neuronal cells.

1.6Implications of the Cross Talk between Estrogen Receptors and IGF-I Receptors for Brain Aging, and Neurodegeneration

The cross talk between ERα and IGF-I receptor in neural cells discussed in the previous sections is summarized in Figure 1.1. From the analysis of this figure, it is evident that, depending on the levels of estradiol and IGF-I, the transcriptional

Figure 1.1 Summary of the cross talk between ERα and IGF-I receptor in neural cells. When estradiol is present at a subthreshold concentration, IGF-I enhances ERα-mediated transcriptional regulation through the MAPK pathway (1). When estradiol concentration reaches the threshold, both IGF-I and estradiol induce the association of ERαand IGF-I receptor in a macromolecular complex in which several components of the PI3K/Akt/GSK3β signaling are present (2). In this scenario, GSK3β is detached from β-catenin, which enters the cell nucleus (3), binds LEF family transcription factors and activates transcription (4). β-catenin can also bind ERα and inhibit ERα-mediated transcriptional regulation (5).

Acknowledgment

The authors acknowledge financial support from the Spanish Ministerio de Ciencia e Innovaci´ on (grants BFU 2008-02950-C03-01 and BFU 2008-02950-C03-02).

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