Estrogen — Mystery Drug for the Brain?: The Neuroprotective Activities of the Female Sex Hormone

244 Pages·2001·5.837 MB·English

by  Priv.-Doz. Dr. rer. nat. Christian Behl (auth.)

Christian Behl
Estrogen - Mystery Drug for the Brain?
The Neuroprotective Activities
of the Female Sex Hormone
Springer-Verlag Wien GmbH
Priv.-Doz. Dr. rer. nat. Christian Behl
MPG-Nachwuchsgruppe, Max Planck Institut fur Psychiatrie, Munich, Germany
This work is subject to copyright.
All rights are reserved, whether the whole or part of the material is concemed, specificalIy
those of translation, reprinting, re·use of illustrations, broadcasting, reproduction by
photocopying machines or similar means, and storage in data banks.
Product Liability: The publisher can give no guarantee for alI the information contained in
this book. This does also refer to information about drug dosage and application thereof.
In every individual case the respective user must check its accuracy by consulting other
pharmaceuticalliterature. The use of registered names, trademarks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from
the relevant protective laws and regulations and therefore free for general use.
© 2001 Springer-Verlag Wien
Originally publi5hed by Springer-Verlag Wien New York in 2001
Softcover reprint of the hardcover 15t edition 2001
Typesetting: H. Meszarics • Satz & Layout • A·l200 Wien
Printed on acid·free and chlorine·free bleached paper
SPIN: 10775877
With 50 Figures
CIP-data applied for
ISBN 978-3-7091-7254-4 ISBN 978-3-7091-6189-0 (eBook)
DOI 10.1007/978-3-7091-6189-0
This book is dedicated to my children
Alina and Tiana
Preface
I first became acquainted with the neuroprotective activities of the female
sex hormone estrogen in 1995 when I was investigating the influence of
various steroid hormones on the survival of neurons. I found that estrogen
(17~-estradiol, the physiological active compound) can protect cultured
neurons against cell death induced by oxidative insults. Just like the well
known antioxidant vitamin E, estrogen can function as a neuroprotective
antioxidant, but in contrast to the former, estrogen is a hormone, serving
many functions within the body, including the brain, where estrogen recep
tors are also located.
This book traces six years of work devoted to gaining an understanding
of the manifold neuronal activities of estrogen: the hormone that plays a
powerful role in the brain, acting both dependent on, and independent of,
receptors; the steroid that interacts with cellular membranes, changing
neurotransmission; the antioxidant that prevents oxidative nerve-cell
death, and the drug used in estrogen replacement therapy. As such, the book
represents a collection of data reflecting current understanding of the
various roles estrogen plays in the brain. The aim was to bring together
molecular and cellular findings with clinical knowledge, establishing a link
therefore between basic and clinical science. For those less familiar with
molecular and cellular experimental methods and language, basic tech
niques are, at certain points, briefly explained.
To write a book on such a topical subject as the neuroprotective activi
ties of the female sex hormone estrogen is a great challenge, for typical of
hot topics in science, the literature is changing on an almost daily basis. It
may therefore be that certain published findings appreciated by one or the
other reader are not included here. I have, however, done my utmost to cover
all the published work believed to be essential to the topic, and reference is
frequently given to outstanding reviews of recent date that discuss certain
topics in greater detail. Nevertheless, although it was my aim to achieve a
well-balanced selection, the personal element involved cannot be denied.
Scientific work involves team-work, and my thanks go to a number of
people, first and foremost to past and present members of my working group,
who have shared my enthusiasm for, and interest in, the role played by
estrogen in neurons: Bernd Moosmann, Dieter Manthey, Frank Lezoualc'h,
VDI Preface
Ayako Yamamoto, Barbel Berning, Martina Graf, Thomas Skutella, Mauro
Sparapani, Elke Hauschildt, Stefanie Engert, Monika Schafer, Nadia
Kosubek, Andreas Klostermann, Stefanie Heck, Elisabeth Gull and Sharon
Goodenough. I am also grateful to the following people for collaborations,
discussions, advice and support over the last years: Florian Holsboer, Beat
Lutz, Christian Krieg, Helmut Vedder, Alexander Baethmann, Andreas
Beck, Matthias M. Weber, Wolfgang Burgmair, Helmut Roth, Benjamin
Wolozin, Dave Schubert and Michael Jurgs.
Scientific work also needs funding, and my sincere thanks go to the
following organizations and foundations without whose support my group's
work would not have been possible: Max Planck Society, the German
Research Association (Deutsche Forschungsgemeinschaft, DFG), the Euro
pean Union, Bayer AG, Deutsche Hirnliga e.V., Alzheimer Forschungs
initiative e.V., Deutscher Stifter Verband (Woort-Stiftung and Heller-Stif
tung), Firma HERMES, Stiftung VERUM.
Last but not least I would like to thank Helga Ruster for all the support
given.
Munich, November 2000 Christian Behl
Contents
General abbreviations ... ........ .................... .............. ................................. XIII
1. Introduction ................................................................... ..................... 1
Estrogen - more than "just" a female sex hormone ......................... 1
Estrogen is a hormone: but what are hormones, anyway? ............... 2
A little history .... .............. ............. ........... ......... ............. ...... .............. 4
In the beginning there was a physiological function ... . ....... ....... 4
... then there was the chemical structure... ..... ........... ... .............. 5
... an estrogen binding-protein ... ................................................. 6
... and finally there was the cloning of the first estrogen
receptor .......................................................................................... 7
How do hormones act? ....................................................................... 9
Hormones ........... ................. .......................................... ........ ........ 10
Estrogen - THE sex hormone and more ............................................ 13
2. Estrogen is a steroid ............................................................................ 16
Production of sex hormones in the gonadal glands ...... ...... ....... ....... 16
Biosynthesis of sex hormones ............................................................ 16
Hormonal changes during the female puberty and the
menstrual cycle ....... .......... ..... ..... ................ ................ .... .............. 20
Transport of estradiol in the bloodstream and catabolism ......... 21
3. Estrogen acts via receptors ....... .......................... ....... ............. ....... ..... 25
"Estrogen's classics" - the genomic pathway of
estrogen action ..... ....... ....... ...... ........ ...... ........... .... ....... .......... .... ......... 25
Steroid receptors have a complex protein structure .................... 28
Another level of complexity: estrogen acts via two ERs
(ERa and ER~) ... .... ......... ....... ....... ....... ....... ... ...... ............. ....... ....... 30
ERa and ER~: a basic comparison ............ ... ...... ...... .... ... .............. 34
The structural domains of ERa and ER~ ............ ....... .... .... .......... 36
Modulation of the estrogen receptor function .................................. 38
Interaction of the ER with co-activators and co-repressors:
of RIPs, RAPs and DRIPs .............................................................. 44
x
Contents
Selective estrogen receptor modulators - SERMs ....................... 47
To be or not to be? Are there membrane ERs? ................................. 49
4. "Non-classical" activities of estrogen ............................................... 52
Rapid non-genomic effects compared to slow genomic
effects of steroid hormones: what makes the difference? ............ 52
Rapid effects of estrogen ..... ................... .......................... ............. 53
Structure-dependent effects: estradiol as antioxidant ...................... 54
Reactive oxygen species (ROS): normal byproducts of
life under oxygen ....... .............. ....................................... ............... 54
Antioxidant defense lines of the cell ............................ ............... 56
Estradiol is an antioxidant similar to a-tocopherol (vitamin E). 57
Dietary phenols and the blood-brain-barrier ............................... 59
5. General physiological activities of estrogen ..................................... 62
Lessons from the ERKO-mice ....................................................... 63
6. Estrogen's actions in the brain ........................................................... 67
Estrogen receptors in the brain...................................................... 67
Neuroactivities of estrogens in brain areas outside the
hypothalamus: the effect of sex differences .................... ............. 68
Effects of estrogen on the cholinergic system ............................. 69
Effects of estrogen on the serotonergic and
catecholaminergic system ............................................................ 72
Activities of estrogen on glial cells .............................................. 74
Are there gender differences in brain function? ................................ 76
Sexual differentiation and gross gender differences in
brain structure and function ......................................................... 76
Sex differences in the function of the hippocampus ................... 77
"Non-classical" activities of estrogen in the brain ........................... 79
Estrogen as "neuroactive steroid" and estradiol's non-genomic
effects at neuronal membranes .... ................................................ 79
Estrogen's "cross-talks" with the intracellular signaling
in neurons ....... ....... ...... ....... ....................................... .................... 84
Estrogen and MAP kinase signaling ............................................. 85
Estrogen's "cross-talk" with other signal pathways
in neurons .. ...................... ... ......................... .................................. 89
Estrogen is a phenolic antioxidant .. ........................... .................. 91
The pathogenetic role of oxidative stress in the eNS ................ 91
The brain is particularly sensitive to oxidative stress ................ 92
7. Protection of the brain by estrogen ................................................... 95
Estrogen as drug for the brain? ........................................................... 95
Contents XI
Menopause, and estrogen replacement therapy (ERT) ...................... 96
ERT for age-related degenerative diseases: general remarks ....... 99
Estrogen and human diseases: general beneficial effects
of estrogen ........................................................................................... 101
Estrogen and arteriosclerosis ........................................................ 101
Estrogen and osteoporosis ............................................................. 103
Estrogen as a drug for the treatment and prevention of
brain diseases? ..................................................................................... 105
Effects of estrogen on cognition ............ ....................................... 105
Estrogen in neuropsychiatric disorders ............................................. 109
Neurodegenerative disorders - Alzheimer's Disease .................. 109
What is the cause of AD? .............................................................. 110
Various AD-hypotheses ................................................................ III
The estrogen-Alzheimer link ....................................................... 119
Parkinson's Disease ...................................................................... 123
PD and estrogen ............................................................................ 125
Novel approaches for the treatment of PD .................................. 127
Stroke ............................................................................................. 127
Stroke and estrogen ......................... .............................................. 128
Schizophrenia ................................................................................ 130
Depression ..................................................................................... 132
To replace or not to replace? ERT and breast cancer risk ........... 136
8. Nerve cell protection by estrogen: molecular mechanisms ............ 142
Life is difficult, at the cellular and molecular level, too .............. 142
Protective effect of estrogen in cultured neuronal cells ................... 144
Mechanisms of nerve cell death ................................................... 144
The two main routes to cell death: apoptosis and necrosis ........ 145
Executioners of apoptosis: caspases ............................................. 147
How to detect apoptosis? .............................................................. 149
Is there apoptosis in Alzheimer's Disease? .................................. 151
Apoptosis in post-mortem AD brain tissue ................................. 151
Apoptosis and necrosis of nerve cells in culture (in vitro) ......... 151
AD genetics and apoptosis ...... ...................................................... 152
Investigations of estrogen's neuroprotective activities
in vitro ........................................................................................... 155
Intracellular molecular mechanisms of neuroprbtection
by estrogen .......................................................................................... 161
Direct ER-dependent neuroprotection: induction of
neuroprotective genes ................................................................... 161
"Cross-Talks" of estradiol with neuroprotective signaling ........ 163
MAP-kinase signaling ................................................................... 163
Phosphatidylinositol3 (PI3)-kinase ............................................. 167
XII Contents
NF-KB ............................................................................................. 168
NF-1d3 is an oxidative stress-responsive transcription factor ..... 169
NF-KB has anti-apoptotic and pro-apoptotic activities ............... 171
Cyclic AMP/ CREB-signaling .............. .................. ........................ 172
Intracellular Ca2+ levels and electrophysiology ........................... 173
Estradiol is a neuroprotective antioxidant: ER-independent effects. 174
Oxidative stress as a general trigger of nerve cell death ............. 175
Oxidative stress in neurodegeneration ........................................ 175
Estradiol is a neuroprotective antioxidant ................................... 176
9. Outlook ............................................................................................... 182
Estrogen's neuroprotective target genes and estrogen's effects
on neuronal stem cells................................................................ ........ 182
Following the neuroprotective trace of estrogen ......................... 182
DNA-array/gene chip technology and expression profiling ........ 183
Screening DNA-arrays/gene chips to identify estrogen
target genes .................................................................................... 184
Estrogen and stem cells ...................................................................... 186
What are stem cells? ..................................................................... 186
Stem cells in the brain - the concept of mammalian neural
stem cells and estrogen's effects on neural stem cells ................ 187
Estrogen modulates neural stem cell generation ........................ 189
Final remarks: neuroprotection by estrogen ..................................... 190
10. References ........................................................................................... 192
Subject index ............................................................................................ 225