| ironjustice@aol.com 2005-05-29, 8:54 am |
| Researchers prevent post-traumatic brain damage
In animal studies, researchers from Georgetown university Medical
Center have shown how traumatic brain injury leads to loss of brain
function--and found that an experimental drug can stop the damage and
promote recovery.
In a study published in the Proceedings of the National Academy of
Sciences (PNAS), the researchers say their findings may hold promise
for the treatment of human traumatic brain injury, a condition they say
affects almost half a million Americans a year and which is currently
untreatable.
"Our study suggests that it might be possible to effectively prevent
much of the injury-induced brain damage," said the study's principal
investigator, Alan Faden, MD, Professor of Neuroscience, Neurology and
Pharmacology at Georgetown university Medical Center, and Director of
the Laboratory for the Study of Central Nervous System Injury.
"We always have to be cautious in predicting human outcome from a study
in rats, but the prevention of brain damage that we saw in this study
is nothing short of remarkable," he said. Rats untreated after head
injury were left 28 days later with a large hole in their brain from
death of cells surrounded by a scar, whereas the brains in those rats
treated with the experimental drug, Flavopiridol, were nearly intact,
with cognitive and motor function recovered, Faden said. "These rats
were no different from the ones that had not experienced brain injury,"
he said.
The approach that Faden and his research team have taken was suggested
by findings from extensive gene studies conducted at Georgetown. Rather
than trying to stop the earliest damage that results from the direct
mechanical injury--the approach that is now most often used
clinically--the Georgetown researchers took the tactic of trying to
limit a second, and much larger, "wave of damage" which they have found
usually peaks from 24-72 hours after injury. During this time, "glial"
cells, which provide support and nutrition to neurons (the nerve cells
that pass information throughout the brain) are pushed to divide
extensively, producing scar tissue, Faden said.
Earlier work by the researchers had pinpointed genes that were turned
on or off after trauma to the brain or spinal cord, and many of these
were found to be involved in activating the "cell cycle," which is
required for glial cells to grow and divide. This proliferation
produces a "glial scar" that can limit recovery. The same process also
activates a type of glial cell, called microglia, that are involved in
brain inflammation after injury.
At the same time, the cell cycle in neurons is activated, but because
these nerve cells can no longer divide, they die. Combined with
inflammation, this wave of damage then continues to progressively kill
vital brain cells, the researchers have found.
"We reasoned that if you can shut down this delayed response to injury,
then the lesion won't spread, the scar won't form, and you could save a
lot of tissue that would have died," said Simone Di Giovanni, MD, PhD,
an Instructor in Department Neuroscience and first author on the paper.
To stop this damage, the researchers chose to test three drugs
(flavopiridol, roscovitine and olomucine) that have been specifically
designed to halt activation of the cell cycle. All three worked to stop
progressive damage when tested in laboratory cell cultures. They then
examined the use of flavopiridol in an experimental rat model of
traumatic brain injury.
Flavopiridol, an anticancer drug, has already been tested in humans,
but has not been proven successful because of the toxicity associated
with sustained use, said Di Giovanni. But the researchers thought that
it might work, and with limited side effects, if the drug was used just
once.
So, in this study, they delivered flavopiridol to the animals 30
minutes after brain injury and found that it reduced expression of
proteins that activated the cell cycle, thus limiting growth of the
glial scar and formation of an inflammatory response. The size of the
lesion was reduced by more than 80 percent, compared to rats who were
not given the drug, and that resulted in a "remarkable improvement in
tissue preservation and behavioral outcome," said Di Giovanni.
Further work now shows that a beneficial response can be achieved in
the rats even if the drug is delivered 24 hours after brain injury.
"This supports the concept that we now need to target the cell cycle in
brain injury, whether it is with this drug or others," Faden said.
Eventually, the researchers hope to use a drug of this type right after
trauma, perhaps through an injection via the nasal passages--an idea Di
Giovanni says the group is exploring.
>From Georgetwon University/
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Tom
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