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Antioxidant Cuts Stroke Damage in Mice

Vitamin C precursor works even hours after attack

MONDAY, Sept. 24, 2001 (HealthDayNews) -- Doctors hoping for a new weapon to add to the limited arsenal available to treat ischemic stroke may be in luck.

New research in mice suggests that an antioxidant compound called dehydroascorbic acid -- the precursor to vitamin C -- can cross the critical barrier between the bloodstream and the brain and reduce the damage caused when a blood clot plugs an artery, halting blood flow to a part of the brain.

The findings appear in the Sept. 25 issue of the Proceedings of the National Academy of Sciences.

Every year, approximately 750,000 Americans suffer a stroke, and almost 160,000 of those attacks are fatal. Ischemic strokes make up about 83 percent of all stroke cases.

There is only one existing therapy available for patients who have suffered an ischemic stroke. But the therapy, called tissue plasminogen activator (or tPA), can be given only after brain imaging scans confirm a stroke. In addition, tPA can sometimes cause bleeding in the brain that actually worsens the patient's condition.

When the blood supply is cut off to brain tissues during an ischemic stroke, restoring blood flow quickly is critical. But paradoxically, the return of oxygenated blood triggers an inflammatory response that can kill partially damaged cells.

One of the factors that play a role in this inflammation is the release of harmful free radicals by the body's immune cells. Antioxidants, like vitamin C, are thought to control the production of free radicals. But vitamin C cannot cross the blood-brain barrier that normally protects the brain from harmful compounds.

Now researchers at Columbia University have shown that dehydroascorbic acid (DHA), the oxidized form of vitamin C, can cross the blood-brain barrier in an mouse model of ischemic stroke. Once it crosses the blood-brain barrier, the DHA is converted to vitamin C. Moreover, mice treated with DHA appear to be better protected from the brain damage caused by stroke.

First, the researchers caused ischemic stroke in mice and injected DHA intravenously into the animals. Autopsies of the mice revealed that, unlike vitamin C, DHA sneaked past the blood-brain barrier.

The next step was testing the effect of the DHA. The researchers induced stroke in a group of mice, giving some of them a range of concentrations of DHA, while others received another antioxidant or a placebo.

Animals received the treatments either 15 minutes or three hours after the stroke, and were monitored for the severity of brain tissue damage, cerebral blood flow, neurological impairment and mortality.

DHA was the only therapy that appeared to have a significant effect. On average, mice that received DHA 15 minutes after their stroke showed a sixfold reduction in brain tissue damage and exhibited less neurological impairment than mice that received the other antioxidant or the placebo.

The protective effect appeared to extend also to mice treated with DHA three hours after the stroke.

Mice that received the highest concentration of DHA showed a ninefold reduction in brain damage compared to animals that received a placebo. These mice also showed the least neurological impairment and doubled their cerebral blood flow 24 hours after the stroke. Animals that received the highest dose of DHA were also the least likely to die after a stroke.

"We finally have an antioxidant that's actively transported across the blood-brain barrier," says senior investigator Dr. E. Sander Connolly, Jr., an associate professor of neurological surgery. "The advantage of this is that it appears to be so safe and has a long treatment window."

"It's so safe that we think that you could give it even if you weren't sure if a patient was having a stroke," he adds. "You wouldn't have to get a CAT scan to prove that it's a stroke before you gave this medicine."

"It fits with a lot of literature showing that antioxidant treatment can be good for at least animal models of stroke," notes John Wilson, a professor of physiology at the University of Western Ontario who is familiar with the study. "I was really impressed that they could give the DHA three hours after the stroke and still see smaller [stroke], decreased mortality and less neurologic deficits on the behavioral tests. That could be potentially clinically applicable."

However, cautions Wilson, "there is a lot of literature of not just positive effects, but also negative effects of giving large doses of vitamin C and large doses of DHA." He says that in older studies, massive doses of DHA were used to destroy the pancreas in animals in order to cause diabetes. In one study, large injections of DHA caused irregular heartbeats that killed rodents.

He also points out that the DHA solution used in this study was 95 percent pure, and the effect of contaminants in the remaining 5 percent are unclear. However, Connolly says that this solution is for use only in mice, and that any solutions made for humans would be different.

There are several risk factors for stroke, only some of which can be controlled. The risk of stroke doubles with each decade past the age of 55, and being male or black increases the risk slightly. Coronary heart disease, diabetes and high blood pressure increase the risk of stroke, as do smoking, being overweight, or drinking.

Connolly and Wilson agree that the need for new ischemic stroke therapies is urgent. "The suffering from this disease is horrible," says Connolly. "And the complication rates from tPA are not insignificant."

"Essentially, we now have a vitamin that's very safe that can be given to protect animals from stroke," says Connolly. "The question is, can we now give that same vitamin to humans to protect them from stroke?"

The team is now planning studies to test DHA in animals whose neurological systems more closely resemble the human brain.

What To Do

Because speedy treatment is crucial, knowing the warning signs of stroke is essential. Check the Web sites for the American Stroke Association or the National Stroke Association for tips.

You can find more general information about stroke from the National Institute of Neurological Disorders and Stroke.

SOURCES: Interviews with E. Sander Connolly, Jr., M.D., associate professor of neurological surgery, Columbia University, New York; John X. Wilson, Ph.D., professor of physiology, University of Western Ontario, London, Ontario; Sept. 25, 2001, Proceedings of the National Academy of Sciences
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