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Source: Purdue university Released: Mon 17-Apr-2006, 16:35 ET
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Hypertension Drug Reverses Death of Cells
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Medical News Keywords
CELLS NERVE-CELLS REVERSE-DAMAGE MEDICATION HYDRALAZINE PARALYSIS
NEUROLOGY SPINAL-CORD INJURY STROKE DISEASES TOXIN ACROLEIN HEALING
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Description
Purdue university researchers have identified a drug commonly used to
treat hypertension that may also reverse damage from spinal cord
injuries, cancer and Parkinson's disease. Riyi Shi (REE-yee SHEE) and
Richard Borgens found that hydralazine, a medication that relaxes veins
and arteries, may be an antidote for acrolein, a deadly toxin that is
produced after a nerve cell is injured.
Purdue News Service photo/David Umberger
Riyi Shi, an associate professor in basic medical sciences and
biomedical engineering at Purdue, uses a recording chamber to test the
loss of function in a spinal cord sample due to the presence of a toxic
chemical called acrolein. Shi, a physician, is with the School of
Veterinary Medicine and Weldon School of Biomedical Engineering.
Newswise - Purdue university researchers have identified a drug
commonly used to treat hypertension that may also reverse damage from
spinal cord injuries, cancer and Parkinson's disease.
A research team led by Riyi Shi (REE-yee SHEE) and Richard Borgens
found that hydralazine, a medication that relaxes veins and arteries,
may be an antidote for acrolein, a deadly toxin that is produced after
a nerve cell is injured.
New findings based on research at the cellular level are detailed in
two studies published in the Journal of Neuroscience Monday, April 17.
In the first article, researchers examine how acrolein attacks and
kills cells. In the second article, they demonstrate that cell death
caused by acrolein (a-KRO-le-an), a byproduct of an injury, can be
reversed when hydralazine is administered.
"This is probably the most important fundamental discovery we have made
at the Center for Paralysis Research because we are saving nerve cells
from death," said Borgens, Mari Hulman George Professor of Applied
Neurology in the School of Veterinary Medicine and founder of the
paralysis research center where the research was conducted.
"Initially we may use this discovery for spinal cord injury and stroke,
but we can expect further studies will look at how it works against a
whole spectrum of injury and disease," he said.
Purdue researchers collected data on acrolein from cell cultures and
found that the potent toxin can destroy entire groups of cells in less
than 12 hours. But they also determined that the cells would survive if
the toxin were treated with hydralazine that acts very much like an
antidote, Borgens said.
"We analyzed other natural toxins as well, and our success has been
remarkable," Borgens said. "We found that more than 80 percent of the
cells can be saved with hydralazine."
Acrolein stays in the body for days and is responsible for secondary
damage that keeps injured cells from healing. The idea to use
hydralazine against acrolein is a logical extension of research on the
toxin, such as the use of a beta blocker against high blood pressure or
chicken soup for a cold, Shi said.
"Acrolein is one of the causes of free radicals that are known to
damage cells, so it makes sense to stop them from ever being produced,"
said Shi, who is associate professor of basic medical science in
Purdue's School of Veterinary Medicine. "With hydralazine, we are
attacking the root of the problem rather than the symptom."
Acrolein is a type of cell toxin called an aldehyde; and the drug,
hydralazine, is effective because it has the ability to trap aldehydes
and stick to them. Once hydralazine binds to the aldehyde, the toxin is
neutralized, deactivated and secreted, Shi said.
The Purdue researchers started looking at alternative methods to save
cells because other studies that had tried to use antioxidants to
deactivate free radical molecules had failed in human clinical trials
in traumatic brain injuries, strokes and spinal cord injuries.
"If we intervene early enough, we may have the ability to slow down the
process of diseases, such as Alzheimer's and Parkinson's, which would
be significant," Shi said. "If we can prevent these diseases from
getting worse, we can give people a better quality of life."
Peishan Liu-Snyder, who graduated last summer and will be a
post-doctoral fellow at Brown university in June, also was part of the
Purdue research team. She became interested in research at the Center
for Paralysis Research when it focused on the use of liquid polymers
that prevent nerve cells from rupturing, enabling them to heal
themselves.
"We found hydralazine works well after the initial injury period
because it targets the secondary injury process," said Liu-Snyder. "It
binds to the acrolein to inactivate its toxicity."
The research on hydralazine is now in the animal-studies phase.
In the laboratory, hydralazine treatments were added to cell cultures
damaged by acrolein, and the deterioration of the nerve fibers was
stopped. But hydralazine is not suitable for injury victims because it
lowers blood pressure, and it is not likely to be the final solution,
Borgens said. Researchers at the Center for Paralysis Research are
teaming with department head Stephen Byrn, and Dan Smith, a
post-doctoral fellow, both from industrial and physical pharmacy in
Purdue's college of Pharmacy, Nursing and Health Sciences, to develop
new drugs based on the activity and structure of hydralazine.
"Hydralazine is a remarkable drug, but it's not suitable for cases of
traumatic injury where the last thing you want to do is lower blood
pressure," Borgens said. "We've embarked on a program now to build a
new drug that will do better job than hydralazine and not carry with it
any unwanted side effects. We either have to make something completely
different or else combat blood-pressure issues with other medications."
One other laboratory, the university of Adelaide in Australia, is
studying the effects of hydralazine on natural poisons. While Purdue
researchers are looking at hydralazine's effect on acrolein in nerve
cells, the Australian lab is concentrating on the molecular mechanisms
to determine how it works.
The Center for Paralysis Research was established in 1987 both to
develop and to test promising methods of treatment for spinal cord
injuries. The center uses its close affiliation with the Department of
Veterinary Clinical Sciences in Purdue University's School of
Veterinary Medicine to move basic laboratory methods into clinically
meaningful veterinary testing.
This research was funded in part by the National Institutes of Health,
predoctoral fellowship funds, the State of Indiana, and gifts from Mari
Hulman George and Helen Skinner, as well as general funds from Purdue's
Center for Paralysis Research.
Writer: Maggie Morris, (765) 494-2432, maggiemorris@purdue.edu
Related Web sites:
Center for Paralysis Research: http://www.vet.purdue.edu/cpr/
School of Veterinary Medicine: http://www.vet.purdue.edu/
Journal of Neuroscience: http://www.jneurosci.org/
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=A9 2006 Newswise. All Rights Reserved.
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http://circres.ahajournals.org/cgi/...t/full/95/2/162
Published online before print June 10, 2004,
doi:10.1161/01.RES.0000134924.89412.70
This Article
(Circulation Research. 2004;95:162.)
=A9 2004 American Heart Association, Inc.
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Molecular Medicine
Novel Mechanism of Action for Hydralazine
<<snip>>
suggesting hydralazine is a sufficiently powerful chelator to bind
enzyme-associated iron under physiological conditions
<<snip>>
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