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.
The San Francisco Veterans Affairs Medical Center has been a primary affiliate of University of California, San Francisco since 1974. The UCSF School of Medicine and the SFVAMC collaborate to provide education and training programs for medical students and residents at SFVAMC. SFVAMC maintains full responsibility for patient care and facility management of the medical center. Physicians at SFVAMC are employed by the Department of Veterans Affairs and also hold UCSF faculty appointments.
Journal
Proceedings of the National Academy of Sciences