Plant-derived chemicals prevent brain cell death, suggesting potential new stroke drugs

Two plant-derived chemicals can reduce the damage from a simulated stroke in
cultured mouse brain cells, according to a study from SFVAMC researchers. 
Further research might lead to a new class of stroke drugs, the researchers
said.

The chemicals work by shutting down the enzyme PARG (Poly-ADP-Ribose
Glycohydrolase), which contributes to cell death in the wake of a stroke, said
the study’s lead author Raymond Swanson, MD, acting chief of neurology at San
Francisco Veterans Affairs Medical Center and UCSF associate professor of
neurology.

“By inhibiting PARG we can protect brain cells from the type of cell death that
happens during a stroke.  This same death mechanism is seen in several other
disorders, such as diabetes, inflammation, and heart attack,” Swanson said.

A different enzyme that acts on this mechanism has already attracted the
interest of a biotechnology company, Guilford Pharmaceuticals.  The company has
patented inhibitors of PARP, an enzyme that works with PARG, and they are
working to develop drugs for stroke and other disorders, according to the
company’s web site.

And although Swanson said it’s still too early to bet on PARG inhibitors as
possible stroke drugs, the results are promising.  “In our studies, PARG
inhibitors were at least as effective at preventing cell death as PARP
inhibitors, and they appeared to be more potent as well,” he said.

The study was published in the October 9 issue of the Proceedings of the
National Academy of Sciences.

The two chemicals tested in the study were plant-derived molecules called
tannins: gallotannin, which can be extracted from green tea leaves or pine
cones, and nobotanin B, from a flower that grows in Japan. 

Because these tannins were known to inhibit PARG, Swanson and his colleagues
suspected they might prevent the death of neurons due to oxidative stress, a
condition that damages the cell’s DNA after a stroke. 

Normally, PARG works together with PARP to alert a cell that its DNA has been
damaged.  PARP builds a tag that marks the location of the damage, and PARG
breaks down the tag.  This repetitive buildup and destruction of these markers
allows the cell’s DNA repair machinery to find the damage and fix it. 

However, after a stroke this repair signaling process becomes over-active, and
it eventually depletes the cell’s energy production system, Swanson explained.
This depletion kills the cell.

In the experiments, the researchers tested the PARG inhibitors on two types of
brain cells, and found that they were effective against a variety of chemicals
that cause massive DNA damage.  For instance, when cultured neuron cells were
treated with peroxide, more than 70 percent of them died.  Inhibitors reduced
that death toll to 20 percent.

Future experiments, according to Swanson, will test PARG inhibitors in an
animal model of stroke.  They will also try to develop smaller versions of the
tannin molecules, because large molecules cannot pass from the blood into the
brain. 

“What matters is whether or not you can get the drug to where it’s needed.  And
we’re optimistic that we will be able to make PARG inhibitors that can pass
into the brain,” he said.

Another important criteria will be whether the drugs are effective several
hours after a stroke, when most stroke patients seek treatment. “Many drugs
look very good when you give them ten minutes after the stroke, but they’re not
so effective at the six hour mark,” Swanson said.

Co-author’s on the study included: Weihai Ying, PhD, Mary Sevigny, PhD, and
Yongmei Chen, PhD, all UCSF postdoctoral fellows in neurology at SFVAMC.

Swanson’s lab works with several other SFVAMC labs as part of a VA Research
Enhancement Award Program (REAP), a national program designed to train new
investigators and promote interdisciplinary collaborations within the VA
research community.  Swanson is director of the cerebrovascular REAP.

The research was supported by the Department of Veterans Affairs, and by a
grant from the National Institutes of Health, which was administered by the
Northern California Institute for Research and Education (NCIRE).

NCIRE is one of the fastest growing medical research groups in the nation. 
Founded in 1988, NCIRE now manages more than $30 million in funding from
organizations such as the National Institutes of Health, the National
Aeronautics and Space Administration, and the National Science Foundation. 
Based at the San Francisco VA Medical Center, NCIRE is the largest of the 80
congressionally authorized VA research corporations.

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