Public release date: 16-Jul-2002
Pennsylvania State University
Contact: Valerie Gliem
vgliem at psu.edu
717-531-8606
Penn State
Study identifies new drug target for preserving brain cells
Research suggests that blocking the effects of interleukin-1 will
prevent brain damage
Doctors know that the body's natural response to injury
inflammation can do more harm than good when it comes to the
brain.
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
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