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New Stroke Treatment Works by Reducing Inflammation
Much of the damage from a stroke is caused by the body's unsuccessful attempts to repair the initial brain injury. This destroys additional tissue and makes a bad situation worse. Curb this damage and stroke symptoms should be less severe. But until recently, no one had ever found a way to do so.
Researchers at the Stanford University School of Medicine now report successfully limiting stroke damage in mice by treating them with a naturally occurring protein, alpha-B-crystallin.
The researchers say that the protein limits damage by soaking up the toxic and inflammatory compounds that are produced after a stroke, just like a sponge would. So far, it's been effective in mice when given up to 12 hours after the onset of the stroke. It hasn't been tested yet in humans.
Alpha-B-crystallin is a major component of the eye's lens. It also has other metabolic functions.
A stroke occurs when there's a drastic drop in blood flow to part of the brain. This is most commonly caused by a blood clot but can also happen when a blood vessel in the brain bursts. Either way, the result is oxygen deprivation. Brain tissue suffers damage if deprived of oxygen for more than 60-90 seconds. After three hours, irreversible damage occurs, often accompanied by tissue death.
But much of the physical damage of a stroke can occur much later, up to 24 hours after the stroke's onset. What started as the death of a small amount of brain tissue becomes much larger due to a molecular cascade — a chain reaction that occurs as the brain tries to repair itself and fails. Inflammation is a key player.
Inflammation in the brain leads to nerve tissue damage. As blood flow is restored to the injured area, white blood cells and inflammatory molecules rush in. This leads to production of a number of reactive and toxic chemicals that cause additional tissue to become damaged. This strategy can be useful in other areas of the body, where damaged or dead tissue can be replaced. In the brain, the end result is that a large amount of tissue not originally affected by oxygen loss becomes permanently damaged.
If there were a way to limit this influx of toxic and inflammatory molecules, the nerve damage and other symptoms that accompany a stroke might be much milder. And alpha B-crystallin appears to do just that.
The Stanford researchers found several lines of evidence that alpha-B-crystallin minimizes the damage from a stroke and can be an effective treatment.
They started by comparing the symptoms of experimentally induced stroke in two lines of mice that were genetically similar, except that one lacked the gene for alpha-B-crystallin and did not produce the protein. The alpha-B crystallin deficient mice had more massive lesions (damaged tissue) from the stroke than the normal mice did. They also had worse neurological function than the normal mice after the stroke. But when the deficient mice were given synthetic alpha-B-crystallin, even 12 hours after the onset of the stroke, the size of the brain lesions were smaller.
Additionally, the mice given alpha-B-crystallin produced fewer inflammatory immune signaling molecules and more anti-inflammatory ones than untreated mice did.
In 2007, the researchers found that alpha-B-crystallin could limit the severity of brain damage caused in mice by multiple sclerosis — an autoimmune disease. So there is previous evidence that alpha-B-crystallin can limit damage to brain tissue caused by inflammation.
The question is whether it can do so in humans.
Currently, the only drug approved to treat strokes is tissue plasminogen activator (tPA). It works by dissolving a blood clot that is preventing brain tissue from receiving fresh oxygenated blood. It's only effective if given within 4.5 hours or so of the stroke. And it can't be used at all in hemorrhagic strokes, the type caused by a burst blood vessel. tPA would only make hemorrhagic strokes worse. Alpha-B-crystallin, if proven effective, would work for both strokes caused by blood clots and for strokes caused by hemorrhage.
The idea that reducing the amount of damaged brain tissue will lead to less severe neurological damage after a stroke seems obvious but has not yet been shown to be true in humans. That will require clinical trials.
An article on the study is scheduled to be published online by Proceedings of the National Academy of Science (PNAS) on July 25.
July 28, 2011