A Potential New Approach to Preventing Stroke Damage
A compound already used to treat severe sepsis could open
up a whole new approach for treating stroke, the leading cause
of long-term disability in the nation. The research, reported
in the March issue of Nature Medicine, shows that a
compound known as activated protein C or APC directly protects
brain cells that normally die as a result of a stroke by curbing
the cells' auto-destruct program.
The research, led by Berislav Zlokovic of the University
of Rochester and John H. Griffin of The Scripps Research Institute
(TSRI), opens up a new vista in a field where effective treatments
are scant. While scientists have known some of the molecular
players that contribute to stroke damage, studies with APC
up to now have focused on other effects of the compound, such
as its ability to stop the growth of blood clots and reduce
inflammation. The new work is surprising because it points
to an unsuspected ability of APC to directly prevent programmed
cell death, which has quietly emerged over the past several
years as the key to reducing the effects of stroke.
"This compound is working in a completely unexpected way–it
gives us a new pathway to consider in assessing the damage
done by stroke," says Zlokovic, who is director of the Frank
P. Smith Laboratories for Neurological Surgery Research in
addition to his position at the University of Rochester. "Since
there is currently really only one effective treatment for
stroke which reaches only a small percentage of patients,
we're hopeful that this finding will spur further research
that could help people who will otherwise have lifelong disability
due to a brain attack."
The research was published online on Monday, February 3.
The scientists showed that, in mice that had strokes, more
than 65 percent of the brain cells that normally would die
after a stroke survive because of APC. The compound reduced
the neurological impact of stroke by 91 percent.
"Stroke is a huge problem," says Griffin, a biochemist and
professor of molecular and experimental medicine at TSRI.
"It's the third leading cause of death in this nation. The
morbidity and sadness for people who survive strokes is overwhelming.
If a new therapy could reduce the damage that a brain attack
causes, that would be extremely valuable."
A stroke occurs when blood flow in the brain is interrupted,
cutting off part of the brain from oxygen. Some brain damage
happens immediately, but even when blood flow is restored,
brain cells continue dying for hours or days. The initial
shock from the lack of oxygen stuns brain cells; those that
don't die immediately are plunged into a Hamlet-like "to be
or not to be" drama, where cells decide whether they can survive
or whether they're so damaged that they should kill themselves,
in a process known as apoptosis, for the overall good of the
body.
It's during this live-or-die drama after a stroke that APC
inserts itself, the team shows in the Nature Medicine
paper. APC dramatically decreases the cellular signals that
convince brain cells to kill themselves after a stroke, and
boosts the cellular signals that persuade the cells to survive.
With APC, pro-suicide signals dwindle, and anti-suicide or
anti-apoptosis signals increase.
With funding from the National Heart, Lung, and Blood Institute,
Zlokovic and Griffin's team found that APC has a direct impact
on a molecule known as p53, which is central to the downward
spiral that envelops a cell which has been exposed to low-oxygen
conditions. Normally in such cells, high levels of p53 are
central to a biochemical cascade that results in compounds
that literally chew up a cell's insides. The team discovered
that APC works through two cellular receptors, EPCR and PAR-1,
to cut the level of p53 in damaged cells by 75 percent and
also boosts the proportion of other signals telling a cell
to survive.
Currently there is one treatment available for stroke, a
compound known as tPA (tissue plasminogen activator). TPA
is useful for the 80 percent of strokes that involve a blood
clot, but only if the patient is treated within a few hours.
And tPA actually kills some brain cells. Someday physicians
might be able to use a compound like APC to prevent damage
for more than the few hours that tPA works, or even to minimize
the brain damage that tPA itself causes.
"I'm cautiously optimistic that APC will prove to be extremely
useful in treating ischemic stroke in patients," says Griffin.
"These are very exciting results."
Griffin has had previous experience seeing such basic research
on APC become clinically relevant. Twenty-five years ago,
Griffin was one of the first scientists to purify protein
C, contributing to a body of knowledge about the compound
that led to its use to treat severe sepsis. Later he discovered
two genetic disorders linked to a lack of APC, diseases that
can now be treated because of his discoveries.
In addition to Zlokovic and Griffin, other authors of the
recent Nature Medicine paper include Tong Cheng and
Dong Liu of the University of Rochester, and Jose Fernandez
of TSRI. Key materials for the experiments were provided by
Francis Castellino and Elliot Rosen of the University of Notre
Dame and Kenji Fukudome of Saga Medical School in Japan. Some
experiments were done in collaboration with Socratech Laboratories,
a Rochester start-up company founded by Zlokovic.
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"Stroke
is a huge problem. It's the third leading cause of death in
this nation. The morbidity and sadness for people who survive
strokes is overwhelming. If a new therapy could reduce the
damage that a brain attack causes, that would be extremely
valuable."
—John H. Griffin
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