Scientists hunting for culprits that lead to brain
damage after strokes have discovered that one likely "bad
guy" is actually a "good guy."
In experiments in the laboratory and with mice, the
Johns Hopkins researchers found that the chemical
prostaglandin-E2 protects brain cells from damage. The
finding was completely unexpected, the researchers say,
because prostaglandin-E2 causes damage in other tissues and
is made by an enzyme, COX-2, known to wreak havoc in the
brain after injury. The findings appear in the Jan. 7 issue
of the Journal of Neuroscience.
"It's kind of paradoxical, that the product of an
enzyme that causes damage is itself beneficial," said
Katrin Andreasson, an assistant professor of
neurology and of
neuroscience. "It's possible that future treatments for
stroke might use drugs to block COX-2 and enhance the
effects of prostaglandin-E2, providing sort of a double
whammy of protection.
"Prostaglandins have not previously been implicated in
reducing damage from stroke, so our finding provides a
completely new strategy for tackling and understanding the
condition," she added.
In experiments with individual brain cells and with
brain slices from mice, the researchers discovered that
prostaglandin-E2, or PGE2, one of many related molecules
created by COX-2, protects brain cells traumatized by
overstimulation or by insufficient oxygen. Furthermore, in
genetically engineered mice lacking one of the receptors,
or docking points, for this prostaglandin, stroke damage
was much greater than in normal mice, the researchers
"Together, these results provide very strong evidence
that PGE-2 is indeed protective in the brain even though it
may not be elsewhere in the body," said Andreasson, who
obtained the genetically engineered mice from Richard
Breyer at Vanderbilt University School of Medicine.
After their surprising discovery, the research team
searched for why PGE2 is a "good guy" in the brain. Their
experiments showed that stimulation of PGE2's receptor
increases production of a molecule called cyclic-AMP, which
is known to help the brain. Other effects of PGE2, such as
anti-inflammatory effects, may also contribute to its
protective abilities in the brain, Andreasson said.
"We think that COX-2 products that increase cyclic-AMP
may prove to be protective, like PGE2, while those that
lower cyclic-AMP may contribute to COX-2's known negative
effects on brain damage from stroke," she said. "We're
still working on it."
About 4 million Americans are currently living with
the effects of stroke, in which blood flow and oxygen
delivery to the brain are interrupted by blockage or
breakage of a blood vessel. At first, brain cells are
shocked, not killed, but their chances of recovery decrease
rapidly as time passes.
If given within an hour of the stroke, a drug called
t-PA can prevent extensive damage by dissolving the blood
clot that caused the stroke. However, finding a way to
intervene later on — for patients whose symptoms
aren't immediately recognized or who are more than an hour
from a hospital — could dramatically improve recovery
and reduce the financial burden of strokes, which the
National Stroke Association estimates is roughly $43
billion per year in the United States.
"We still need to determine whether stimulating the
PGE2 receptor hours after a stroke can protect mice from
damage," said Andreasson, who is conducting some of those
studies now. "If so, pursuing this prostaglandin as a
potential clinical target will be of great importance."
COX-2 has a significant role in brain damage after
stroke in mice, and Andreasson has been searching for how
exactly COX-2 causes damage. Scientists know that COX-2 is
involved in creating inflammation, or swelling (drugs like
Celebrex and Vioxx inhibit COX-2 and are widely prescribed
for arthritis and other inflammatory conditions), but its
activity leads to the production of a number of different
molecules that could be more directly responsible for its
effects. Andreasson and her colleagues are continuing to
evaluate the effects of other products of COX-2.
The studies were funded by the American Federation for
Aging Research, the American Heart Association and the
National Institute on Neurological Diseases and Stroke.
Authors on the report are Andreasson, Louise McCullough,
Liejun Wu, Norman Haughey, Xibin Liang, Tracey Hand and
Qian Wang, all of the Johns Hopkins School of Medicine; and
Breyer, of Vanderbilt.