 Mikael Elliasson and Valina Dawson in the lab. |
September 30, 1997
Media Contact: Michael Purdy
Phone: (410)955-8725
E-mail:mpurdy@welchlink.welch.jhu.edu
|
BY FURTHER TRACKING nitric oxide's actions in the
brain, Johns Hopkins scientists report they have figured out what may be a
universal sequence of biochemical events from stroke to brain cell death.
Cell death appears to result from the overactivation of an enzyme called
poly (ADP-ribose) polymerase, or PARP, which lethally depletes energy sources
from the cells, according to Valina Dawson, Ph.D., associate professor of
neurology. When she and her colleagues induced strokes in mice genetically
engineered without a PARP gene, brain damage was dramatically reduced in
comparison to a group of unaltered mice.
"Nitric oxide has long been known to play a role in neuronal damage after
stroke, and now it seems that a candidate pathway for that injury is DNA damage
leading to unusual PARP activation," Dawson reports in the October issue of
Nature Medicine. Nitric oxide does its damage by sabotaging the DNA of nerve
cells. The DNA nicks and breaks activate PARP, which is normally, for the most
part, dormant, she says.
"Clinically, our work suggests that inhibiting PARP may spare nerve cells
from energy loss, thus preventing irreversible damage and providing
protection," says Solomon Snyder, M.D., distinguished service professor and
director of the Department of Neuroscience and an author of the paper.
Paradoxically, in cases of minor damage, PARP acts as a relief squad,
activated to make repairs. But with more substantial damage, such as severe
loss of blood during stroke, PARP can be overactivated. When this happens, it
uses up NAD, the substance PARP acts on, and ATP, the major energy source of
all cells, causing the cell to die of energy depletion.
In the study, researchers first compared brain tissue from the so-called
"knockout" mice, bred in Austria without a PARP gene, to unaltered mice to
measure toxicity caused by interaction with other brain chemicals released in
cases of neurological damage. The tissue from the knockouts were completely
resistant to neurotoxicity. In tissues from the unaltered mice, however,
approximately 65 percent of the cells were destroyed.
They then induced experimental strokes in the mice to evaluate the extent
of resulting brain injury. Tissue damage in the genetically altered mice was
80 percent less than in the unaltered mice.
"The reduction in stroke damage in PARP knockout animals suggests that
PARP inhibitor medications may be useful for treating strokes," Snyder says.
"The reduction in brain damage we observed following blockage of a major brain
blood vessel in the mice without PARP exceeds the protection reported with any
other treatment."
Stroke is the third leading cause of death and disability, affecting 3
million people each year. It occurs when a blood vessel bringing oxygen and
nutrients to the brain bursts or is clogged by a blood clot or some other
particle. Because of this rupture or blockage, part of the brain doesn't get
the flow of blood it needs, and the nerve cells in that section start to die
within minutes. Brain damage from a stroke can diminish the senses, speech and
the ability to understand speech, behavioral patterns, thought patterns, and
memory. Paralysis on one side of the body is common.
Michael Muskowitz and colleagues at the Massachusetts General Hospital have
independently replicated these findings, Snyder says, and will be publishing
their results in the near future.
The study's other authors were Mikael J.L. Eliasson; Kenji Sampei, M.D.;
Allen S. Mandir, M.D.; Patricia D. Hurn, Ph.D.; Richard J. Traystman, Ph.D.;
Jun Bao, Ph.D.; Andrew Pieper; Zhao-Qi Wang, Ph.D.; and Ted M. Dawson, M.D.,
Ph.D.
Johns Hopkins has previously licensed the rights for PARP inhibitors to
Guilford Pharmaceuticals in Baltimore. Under the terms of the previous license
agreement between the Johns Hopkins University and Guilford, Snyder, Valina
Dawson and Ted Dawson are entitled to a share of sales royalties received by
the University from Guilford. The University owns stock in Guilford, with
Snyder and Ted Dawson having an interest in the University share under
University policy. The University's stock is subject to certain restrictions
under University policy. Snyder also serves on the Board of Directors and the
Scientific Advisory Board of Guilford, he is a consultant to the company, and
he owns additional equity in Guilford. This arrangement is being managed by
the Johns Hopkins University in accordance with its conflict-of-interest
policies.
