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Senior Citizen Health & Medicine
New Treatments Given Hours After Stroke Prevent
Brain Injury
Tests with rats
funded by Veterans Health Administration, American Heart Association
December 29, 2006 - Two novel treatments -- a basic
compound found in every cell in the body and an extract of green tea --
may prevent brain damage caused from stroke, according to two studies in
rats led by a researcher at the San Francisco VA Medical Center.
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Senior Citizens See Decrease in Incidence of Stroke
in Last 50 Years
Death within 30 days decreased significantly in men
but not women
December 26, 2006 - The incidence of stroke in the
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stroke has not, according to a study in the December 27 issue of JAMA.
For senior citizens, age 65 and older, the lifetime risk of clinical
stroke by age 90 decreased from 19.5 percent to 14.5 percent in men and
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Both treatments were administered through the nose,
rather than intravenously, the conventional method for delivering drugs
to the brain.
In one study, rats' brains were subjected to
ischemia -- severely reduced blood flow for two hours in a model of
stroke. Researchers then administered nicotinamide adenine dinucleotide,
or NAD+, immediately after "reperfusion," or resumption of blood flow.
Reperfusion is the time when stroke damage actually occurs because brain
cells are suddenly exposed to highly reactive and unstable oxygen
molecules, which are toxic.
The researchers found that NAD+ reduced brain cell
death from reperfusion by 70 to 86 percent compared with rats not given
the treatment, according to lead author Weihei Ying, PhD, a research
scientist at SFVAMC and an assistant adjunct professor of neurology at
the University of California, San Francisco.
The study appears in the January 1, 2007 issue of
Frontiers in Bioscience.
NAD+ plays a number of essential roles in cell
metabolism. One role is supporting the activity of the DNA repair enzyme
PARP-1, which normally repairs cell damage from brain infection. In
response to reperfusion following ischemia or brain trauma, PARP-1 is
overactivated. As a result, it quickly depletes all available NAD+, in a
sense its "fuel," and is unable to repair cell damage, leading to brain
cell death.
In previous studies, SFVAMC researchers including
Ying provided the first evidence that administration of NAD+ can
completely prevent PARP-1-induced cell death in cell culture. The
current study is the first to investigate NAD+ administration as a
potential treatment for brain injury in animal models, and the first to
demonstrate its effectiveness in an animal model, he says.
"Basically, we replenish the NAD+," Ying explains.
"The protective effect is profound."
Administration of NAD+ also significantly reduced
motor impairments commonly observed in rats after stroke, ranging from
involuntary limb bending to inability to walk, says Ying.
Second Study with Green Tea Extract
A second study led by Ying investigated whether
administration of the green tea extract gallotannin, or GT, can protect
against post-ischemic brain damage. In previous cell culture studies by
Ying and other researchers, GT had been shown to inhibit the action of
PARG, an enzyme closely related to PARP-1, and in doing so decrease cell
death under ischemia-like conditions. Ying's study indicates that it
does the same in rats, reducing brain cell death significantly when
administered intranasally up to three hours after reperfusion.
The results of the study were reported at the 2006
annual meeting of the American Society for Neurosciences.
In the same study, Ying and his team also
discovered that intranasal GT completely blocked a secondary
post-ischemic effect associated with PARP-1 activation: the movement of
the protein known as apoptosis inducing factor (AIF) from where it
resides in a dormant state in the mitochondrion the cell's power
plant into the nucleus, where it becomes active and causes the cell
to die.
Significantly, GT provided no protection at all
against either PARG or AIF when administered intravenously (IV). Ying
designed the study in such a way that a comparison could be made of the
efficacy of intranasal and IV drug delivery the first known study to
make such a comparison using an animal model of stroke.
"This finding suggests that the intranasal method
could be more advantageous than IV for delivering a drug for treating
central nervous system diseases," Ying says. "It may get much more of
the drug past the blood-brain barrier."
Ying characterizes both compounds as "promising,"
but speculates that NAD+ has the greater potential as an agent for
preventing brain cell death for several reasons.
"Our experimental results have suggested that NAD+
can produce greater protective effects than GT against ischemia," he
notes. "Plus, NAD+ is a fundamental molecule for cell metabolism, so it
is known to have relatively low toxicity." In addition, he says, NAD+
loss occurs after PARP-1 activation, meaning that NAD+ might be used
later after injury than GT. Ying is currently investigating this
question.
Finally, says Ying, recent studies have suggested
that NAD+ plays an important role in basic biological processes such as
calcium metabolism and aging. He speculates that it might become "a
novel class of drug" for a variety of brain diseases and conditions
including Parkinson's disease, Alzheimer's disease, traumatic brain
injury, and hypoglycemic brain injury.
Ying says that because both compounds provide
significant protection hours after the onset of ischemia, both studies
have important potential implications for treatment of ischemic brain
injury among humans. In current medical practice, treatment during the
first 60 minutes after injury the so-called "golden hour" is
considered crucial if the patient is to survive with minimal damage.
Editors Notes:
Co-authors of the NAD+ study are Guangwei Wei,
PhD, Dongmin Wang, BS, Qing Wang, MD, PhD, Xiannan Tang, MD, Jian Shi,
PhD, Peng Zhang, MD, PhD, and Huafei Lu, PhD, all of SFVAMC and UCSF.
The NAD+ study was funded by the Veterans Health
Administration and by a grant from the American Heart Association that
was administered by the Northern California Institute for Research and
Education.
Co-authors of the GT study are Guangwei Wei, PhD,
Dongmin Wang, BS, Qing Wang, MD, PhD, and S. Scott Panter, PhD, of
SFVAMC and UCSF, and William H. Frey II, PhD, of the University of
Minnesota, Minneapolis, Minn. and Regions Hospital, St. Paul, Minn.
The GT study was funded by the Veterans Health
Administration.
NCIRE is the largest research institute
associated with a VA medical center. Its mission is to improve the
health and well-being of veterans and the general public by supporting a
world-class biomedical research program conducted by the UCSF faculty at
SFVAMC.
SFVAMC has the largest medical research program
in the national VA system, with more than 200 research scientists, all
of whom are faculty members at UCSF.
UCSF is a leading university that advances health
worldwide by conducting advanced biomedical research, educating graduate
students in the life sciences and health professions, and providing
complex patient care.
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