But new research from Steven Levison, Ph.D., associate professor of neuroscience and anatomy, Penn State College of Medicine, explains the cellular and molecular reasons why this is true. Furthermore, his research provides important information that could lead to new drugs to prevent brain cell death after injury or as a consequence of neurodegenerative diseases like Alzheimer's.
Levison's study on mice, published in the July 15, 2002, print edition of Journal of Neuroscience, not only describes an important mechanism by which the body reacts to brain injury, but goes farther to show why inhibiting the effects of interleukin-1 – a protein immune cells release in response to injury – will stop additional brain tissue damage. The article will be released on-line on July 16, 2002.
"The study provides strong rationale for testing IL-1 receptor blocking reagents as treatments for traumatic brain injury and stroke, and even neurodegenerative diseases like multiple sclerosis and Alzheimer's disease," Levison said.
In both mice and humans, IL-1 is a vital component of the injury response. When IL-1 is released into a tissue, it activates scavenger cells known as macrophages to move into the injury site and cause inflammation. Macrophages release substances that kill bacteria and viruses, and they ingest dead cells. They also release IL-1, which signals more macrophages to invade the damaged tissue.
"The macrophage reaction is a good one in regenerating tissues, but in a non-regenerating tissue like the brain, it can be devastating," Levison said.
When macrophages release IL-1 and attract more of the scavenger cells to the brain, they become exited and overactive, causing harm to other cells nearby. This adds to the damage caused by the initial injury and destroys more healthy neurons. Therefore, instead of helping, the release of IL-1 and the subsequent activation of brain macrophages may have additional severe and irreversible consequences for brain function.
To determine whether inflammation would be decreased when IL-1 stimulation is blocked, Levison and his colleagues evaluated brain injury in mice that lacked the capacity to respond to IL-1. In their study of these so-called IL-1 receptor null mice, Levison and his colleagues found that fewer macrophages were attracted to the brain, and that the brain's macrophages, know as microglia, were not as excited and did not produce substances that would harm healthy brain cells.
"These data suggest that cell preservation is achieved by stopping macrophage, or microglial, activation," Levison said. "In addition, the research shows that the initial burst of IL-1 causes more IL-1 to be released, which amplifies the injury response. This causes a runaway inflammation in the brain where you don't want it. It's as David Bowie would put it, 'like putting out the fire with gasoline.' This study helps us understand why inflammation in the brain is not good and specifically why IL-1 is not good for the brain."
Previous studies by a variety of investigators have shown that IL-1 is elevated after traumatic brain injury, multiple sclerosis, Alzheimer's Disease and Downs Syndrome and that mice with reduced IL-1 are significantly protected from ischemic injury – brain damage caused by a lack of oxygen reaching the brain. Other research showed that administering a substance that inhibits IL-1 reduced neuronal death after ischemia.
By establishing the cellular and molecular components of the Central Nervous System injury response, Levison's work reveals why inhibiting IL-1 will protect brain cells from injury and disease. Additionally, this research could lead to new drug therapies to preserve brain tissue in people who've suffered a brain injury or stroke, or have a neurodegenerative disease.
Levison's group is currently using these mice to test his prediction that there will be less damage caused by stroke. In addition to stroke studies, Levison plans to see whether these mice will be less vulnerable to multiple sclerosis-like diseases.
This study was funded by a grant from the National Multiple Sclerosis Society. IL-1 null mice were provided by Immunex, a biopharmaceutical company based in Seattle, Was