AUG 24, 1999, M2 Communications - For several days after a patient
suffers a stroke, brain cells are bombarded with molecular "pro-death"
signals carrying such bad news about the brain environment that the
cells are tempted, even urged by other molecules, to commit suicide.
Many do. It's the main reason why most strokes aren't limited to a tiny
area of the brain but damage a larger region as well.
In a bid to persuade fickle brain cells to live, University of
Rochester Medical Center scientists have enlisted an unlikely ally: the
herpes virus. In an article published August 15 in the Journal of
Neuroscience, the team announces a series of experiments where it used
the virus to modify brain cells from mice, making the cells more
resistant to death after a stroke. Like psychologists talking a
despondent man down from the ledge, scientists kept cells from
preventing suicide by thwarting the molecular machinery normally
involved in persuading cells to self-destruct in a process known as
apoptosis. Once the brain has been traumatized by the low oxygen
levels, or hypoxia, that stroke causes by choking off the blood supply,
it unleashes a flurry of molecular signals encouraging still-healthy
cells to kill themselves, magnifying the effects of the initial attack.
The widespread self-destruction takes places for days or even a week
after the initial stroke. It's a big reason why strokes are the leading
cause of long-term disability in the United States, where there are
about 4 million stroke survivors, roughly the same number of people as
have Alzheimer's disease.
"Stroke is all about how cells deal with hypoxia," says
neuroscientist Howard Federoff, M.D. Ph.D., who did the study with
graduate student Marc Halterman and dermatologist Craig Miller, M.D.
Ph.D. "Do they adapt and survive, or do they withdraw and commit
suicide?" asks Federoff, who has developed a highly advanced system for
using the herpes virus-long the bane of cold sore sufferers
everywhere-to manipulate genes in the nervous system.
Today, the only real treatment for stroke is a set of drugs that
break up the blood clots that cause most strokes. Such drugs are only
useful if patients get to the hospital within a few hours of a "brain
attack," and just a tiny percentage of patients ultimately receives
them. There are no drugs approved for use in humans to help save the
cells in the siege that follows in a broad area known as the penumbra,
the area surrounding the initial site of stroke. "Patients who arrive
at the hospital too late to be candidates for clot-busters might be
candidates for a drug useful during this window of opportunity, to
protect cells that will go on to die if you don't intervene," says
Halterman, who is earning both his M.D. and his Ph.D. at the University
of Rochester School of Medicine and Dentistry.
While dozens of compounds are being studied to help protect brain
cells after a stroke, they are not used clinically because none has
been shown to be both safe and effective in humans, says Curtis
Benesch, M.D., director of the Stroke Program at the University's
Strong Memorial Hospital. "Right now treatment for acute stroke
consists of two things: restoring blood flow, and 'housekeeping'
details, like making sure glucose and blood pressure are at optimum
levels," says Benesch. "A compound to help nearby cells cope with the
shock of low oxygen would give doctors a new way to try to save
patients from the years of disability that a stroke often causes."
As one step toward such a drug, Federoff's team asked the question:
What brings a brain cell to suicide? Through a series of painstaking
experiments funded by the National Institutes of Health, Halterman
showed that two genes that help make cancerous tumor cells tough to
kill are also involved in causing brain damage after a stroke.
The genes, HIF1 and p53, play a vital role in our everyday lives. The
normal version of P53 helps our bodies suppress cancer, and HIF1 helps
us cope with low-oxygen conditions, spurring the bone marrow to produce
more oxygen-carrying red blood cells. Each also plays an important role
in tumor cells, where HIF1 and a mutated copy of p53 help cancer cells
survive in places in the body where oxygen is in short supply, like the
inside of large tumors. In the brain, the Rochester team found that
both HIF1 and p53 play a role in convincing stressed cells to commit
suicide. When the team used the herpes virus to shuttle into brain
cells from mice a modified, defective version of the normal HIF1 gene,
most of the cells opted not to commit apoptosis when stressed by low
oxygen levels. Fewer of the neurons in a cell culture model of stroke
died-about half the neurons that normally would have died survived-when
HIF1('s activity was taken out of the picture.
The scientists suspect that a cell's decision to commit suicide or
not involves signals sent by HIF1 and p53 from the mitochondria, the
cellular energy source that needs oxygen to keep the cell alive. HIF1
acts as an oxygen sensor that helps the cell decide whether to adapt to
hypoxia, or instead activate p53 as part of a built-in suicide program
to kill itself in a violent burst. "If we can understand how that
precise switch is regulated, it would open the door to some very
interesting neuroprotective compounds to treat stroke," says Federoff,
who is also director of the Medical Center's Center on Aging and
Developmental Biology and chief of the Division of Molecular Medicine
and Gene Therapy.
