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| Monterotondo,
Heidelberg, Ulm, Sunday 13 November 2005 |
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| Limiting the damage in stroke |
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| Manolis Pasparakis, EMBL |
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| Oliver Herrmann and Markus Schwaninger, University Hospital and Medical Faculty, Heidelberg |
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| Thomas Wirth, University of Ulm |
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| Bernd Baumann, University of Ulm |
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Press
Release 13 November 2005 [PDF]
[Deutsch]
A cellular signal may determine life or death for damaged brain cells
Scientists at the Universities of Heidelberg and
Ulm and a unit of the European Molecular Biology
Laboratory [EMBL] in Monterotondo, Italy, have discovered
that a specific signal within brain cells may determine
whether they live or die after a stroke. Their study,
published online [November 13] by Nature Medicine,strongly
suggests that new therapies for victims of strokes
could be developed by controlling a molecule involved
in passing the signal.
Strokes lead to death or permanent disabilities
for millions of people every year when an interruption
of the flow of blood to brain cells deprives them
of vital oxygen and nutrients. But the fate of the
cells seems to depend on what happens next. Scientists
discovered that damaged and dying brain cells are
very actively using an internal 'communications
network' known as the NF-κeB signalling pathway.
Cells have many such networks; their function is
usually to switch genes on or off, changing the
chemistry and behavior of the cell. Most drugs work
by interfering with molecules that play important
roles within these networks.
Scientists knew that NF-κeB signaling was
active in neurons, but its function was unclear.
"We had some evidence that in nerve cells,
it could trigger a self-destruction program called
apoptosis," says Markus Schwaninger of the
University of Heidelberg, one of the heads of the
project. "If that was the case, the signal
could certainly be playing a role in the death of
neurons after stroke and other types of brain damage."
To address this hypothesis, Schwaninger's group
had established a sophisticated method of creating
a stroke-like condition in mice, a model that can
be used to investigate new therapies.
What would happen if the activity of NF-κB
in neurons were blocked after a stroke? To test
this, genetic mouse models were required. The group
of Manolis Pasparakis at EMBL's Mouse Biology Unit
developed a strain of 'conditional knockout' mouse
in which a protein called IKK2, which activates
NF-κeB, can be controlled. The researchers
are able to shut down the molecule at any time in
neurons. "More common methods of shutting down
a gene remove it from all tissues, for an animal's
entire life," Pasparakis says. "You can't
do that with NF-κB itself – in other
types of cells the signal has important functions
which are necessary for the animal to survive. So
to test our hypotheses about its role in neurons,
we needed more precise control of the gene."
In parallel, Bernd Baumann and Thomas Wirth at the
University of Ulm had generated two additional mouse
models, which allow the reversible repression or
activation of IKK2 at any time in neurons. "The
unique advantage of this system is that we can specifically
induce or block this signaling pathway at virtually
any time and selectively in neurons," Wirth
emphasizes. Putting all of this expertise together
permitted the researchers to get a clear picture
of IKK2's role after a stroke.
Mice with the hyperactive form of IKK2 in neurons
and too much NF-κeB signalling, they discovered,
suffer even more damage than normal; far more cells
die. But if the IKK2 signal is blocked, damaged
cells stay alive and even seem to recover. The effects
are long-term; neurons in the damaged tissues were
still alive several days after the stroke.
Two factors make the study promising in the search
for treatments for this deadly disease. First, shutting
down the IKK2 signal had beneficial effects even
when it was done a few hours after the stroke. That
is important when thinking about possible human
therapies; it usually takes time for a patient to
reach the hospital. Secondly, the same effects could
be achieved by blocking IKK2 activity with a small
artificial molecule. That's what a drug will have
to do. Human cells have a very similar NF-κeB
signaling network, which means that there is a good
chance IKK2 will do something similar in our own
brain cells. As NF-κeB passes a variety of
other important signals, pharmaceutical companies
have already been developing molecules that target
parts of the signaling pathway.
Press
Releases University of Heidelberg
Source article
IKK mediates ischemia-induced neuronal death
O. Herrmann, B. Baumann, R. de Lorenzi, S. Muhammad,
W. Zhang, J. Kleesiek, M. Malfertheiner, M. Köhrmann,
I. Potrovita, I. Maegele, C. Beyer, J. Burke, M.T.
Hasan, H. Bujard, T. Wirth, M. Pasparakis and M.
Schwaninger
Nature Medicine, 13 November 2005 [online
publication]
Press contact
Sarah Sherwood
EMBL Information Officer, European Molecular Biology
Laboratory, Meyerhofstrasse 1, 69117 Heidelberg,
Germany
Tel: +49 [0] 6221 387-125
E-mail: sarah.sherwood@embl.de
Dr. Annette Tuffs
Press Office, University Hospital and Medical Faculty,
University of Heidelberg, Germany
Tel: +49 [0] 6221 56-4536
E-mail: Annette_Tuffs@med.uni-heidelberg.de
Prof. Dr. Markus Schwaninger
University Hospital and Medical Faculty, University
of Heidelberg, Germany
Tel: +49 [0] 6221 56-37535
E-mail: Markus.Schwaninger@med.uni-heidelberg.de
Dr. Thomas Wirth
Department of Physiological Chemistry, University
of Ulm, Germany
Tel: +49 [0] 731 502-3270
E-mail: thomas.wirth@uni-ulm.de |
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