"It's kind of paradoxical, that the product of an enzyme that causes damage is itself beneficial," says Katrin Andreasson, M.D., 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 adds.
In experiments with individual brain cells and with brain slices from mice, the researchers discovered that prostaglandin-E2 (PGE2), one of many related molecules created by COX-2, protects brain cells traumatized by over-stimulation 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 report.
"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," says 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, says Andreasson.
"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 says. "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," says 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 which 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 of The Johns Hopkins University School of Medicine; and Breyer of Vanderbilt.
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