Countering The Body's Own Harmful Response to Stroke

April 20, 2001

Scientists have found that a compound that recently made headlines for its potential in treating sepsis also holds promise in protecting brain cells from the damage caused by stroke.

Activated Protein C, or APC, helps snuff out a crucial step in the chain of events that can lead to the death of neurons. While brain damage from stroke initially begins with a lack of blood flow to the brain, the damage is increased by a cascade of reactions, including overzealous attempts by the body's own immune system to "fix" the damage. White blood cells are recruited to the stroke site by chemical messengers and try to clean up the damage - but the response often magnifies the injury and can cause a patient's condition to worsen. It's a bit like an over-enthusiastic security guard inadvertently roughing up legitimate guests during an effort at crowd control.

In a study in the April 3 issue of the journal Circulation, scientists report on work in mice which shows that APC can stem the flood of harmful white blood cells into the brain, one key to reducing the effects of stroke. Strokes are the leading cause of long-term disability in the United States, where there are about 4 million stroke survivors.

"The damage from a stroke doesn't happen just because the brain is deprived of oxygen and other nutrients; it's partly a result of the body's response," says lead author Berislav Zlokovic, M.D., Ph.D., of the University of Rochester Medical Center. "The influx of white blood cells into the brain causes tremendous damage. The role of inflammation in inflicting damage to the brain is only recently becoming appreciated."

Zlokovic did the work in collaboration with John Griffin and Jose Fernandez of Scripps Research Institute in La Jolla, Calif., and Masayoshi Shibata, S. Ram Kumar, Arun Amar, and Florence Hofman of the University of Southern California.

For more than a decade Griffin and Zlokovic have studied APC together and have discovered how the compound helps prevent blood clots. Some researchers believe that people who have low levels of APC, a natural compound made by the body that helps prevent blood clots, are more likely to suffer a stroke. Eli Lilly is developing a genetically engineered version of APC for use against sepsis, an often-fatal blood disorder; a study published March 8 in the New England Journal of Medicine showed that APC reduced by 20 percent the rate of death in sepsis patients.

In research sponsored by the National Heart, Lung, and Blood Institute, Zlokovic's team found that in mice that had strokes, animals that were given APC were much more likely to survive than their counterparts that did not receive APC. The animals showed a number of benefits: their brains had more blood flow and less swelling, their blood was less likely to clot, a smaller portion of the brain was affected by the stroke, and their brains contained only negligible levels of white blood cells known as neutrophils. It's this last feature that grabbed the team's attention.

Normally the brain is off limits to extra white blood cells, because the blood/brain barrier keeps toxins and other damaging materials out. Though the cells circulate in the blood that flows through the brain, the blood vessels fail to put out adhesion molecules - the brain's version of a welcome mat - for the cells to latch onto. Without the adhesion molecules, known as ICAM-1 molecules, white blood cells flow right by.

"These white blood cells normally roll along inside the blood vessel, temporarily attaching and then detaching from the vessel walls and moving along with the blood flow," Griffin says. "But if there's damage or inflammation, the white blood cells stick tightly to the wall instead of rolling along. Then if the cells receive certain signals, they start slinking through the vessel wall and into the surrounding tissue."

Those signals come in the form of the adhesion molecules, which act like tiny docking ports. In times of brain damage or stress the molecules suddenly become available, oftentimes within just 15 or 30 minutes of a stroke. These enable white blood cells like neutrophils to gain a foothold in a blood vessel and then migrate into brain tissue

The scientists found that APC suppresses the ICAM-1 adhesion molecules, preventing white blood cells from entering the brain. In the study in Circulation, APC-treated mice had 90 percent fewer white blood cells than their counterparts in the brain tissue surrounding the initial site of stroke.

"Once white blood cells are able to adhere to blood vessel walls, they have an open path to the brain. White blood cells neutralize pathogens, but in the process, they often damage healthy tissue as well. We're trying to restrict this reaction," says Zlokovic, chief of the Division of Neurovascular Biology at the University of Rochester's Center for Aging and Developmental Biology. "APC helps to keep white blood cells under control."

The APC project is part of a wider research effort by Zlokovic, a neurosurgeon who specializes in studying the role of blood vessels in neurodegenerative disorders like Alzheimer's disease and stroke. Last year he showed that blood circulation in the brain plays a key role in the prevention of beta amyloid plaques that speckle the brains of Alzheimer's patients. He and Griffin are continuing their studies to see whether APC might someday become a stroke treatment.

"From the time that blood flow stops to the time that brain cells die, there is a series of complex reactions. Understanding those reactions, which involve inflammation, apoptosis, and other processes, is a very hot topic in research," says Griffin, professor of molecular and experimental medicine at Scripps Research Institute.

Currently, while there are several potential stroke therapies such as APC under development, prevention and rapid treatment are vital, says Charles Francis, M.D., chief of the Vascular Medicine Unit at the University of Rochester's Strong Memorial Hospital. "Controlling risk factors such as high blood pressure is very important. Once a person has had a stroke, they must seek treatment immediately, so that we can use the one drug we have available today, TPA (tissue plasminogen activator), and possibly do some good for the patient."

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