Inflammatory Response in Mild
Traumatic Brain Injury Beneficial During Early Hours
Concussion secrets unveiled as NIH
scientists film early damage and describe brain’s response to injury -
Dec. 9, 2013 - There is more than meets the eye following even a mild
traumatic brain injury, a serious health concern for seniors.
Approximately 22% of all TBI-related hospitalizations involved
adults aged 75 years and older. While the brain may
appear to be intact, new findings reported in Nature suggest that
the brain’s protective coverings may feel the brunt of the impact.
Previous studies have suggested
that immune responses in the brain can often lead to severe damage.
Remarkably, the findings in this study show that the inflammatory
response in a mild traumatic brain injury model is actually beneficial
during the first 9-12 hours after injury.
Using a newly developed mouse
trauma model, senior author Dorian McGavern, Ph.D., scientist at the
National Institute of Neurological Disorders and Stroke (NINDS), part of
the National Institutes of Health, watched specific cells mount an
immune response to the injury and try to prevent more widespread damage.
Notably, additional findings suggest a similar immune response may occur
in patients with mild head injury.
In this study, researchers also
discovered that certain molecules, when applied directly to the mouse
skull, can bypass the brain’s protective barriers and enter the brain.
The findings suggested that, in the mouse trauma model, one of those
molecules may reduce effects of brain injury.
Although concussions are common,
not much is known about the effects of this type of damage. As part of
this study, Lawrence Latour, Ph.D., a scientist from NINDS and the
Center for Neuroscience and Regenerative Medicine, examined individuals
who had recently suffered a concussion but whose initial scans did not
reveal any physical damage to brain tissue. After administering a
commonly used dye during MRI scans, Latour and his colleagues saw it
leaking into the meninges, the outer covers of the brain, in 49 percent
of 142 patients with concussion.
To determine what happens following
this mild type of injury, researchers in Dr. McGavern’s lab developed a
new model of brain trauma in mice.
“In our mice, there was leakage
from blood vessels right underneath the skull bone at the site of
injury, similar to the type of effect we saw in almost half of our
patients who had mild traumatic brain injury. We are using this mouse
model to look at meningeal trauma and how that spreads more deeply into
the brain over time,” said Dr. McGavern.
Dr. McGavern and his colleagues
also discovered that the intact skull bone was porous enough to allow
small molecules to get through to the brain. They showed that smaller
molecules reached the brain faster and to a greater extent than larger
ones. “It was surprising to discover that all these protective barriers
the brain has may not be concrete. You can get something to pass through
them,” said Dr. McGavern.
The researchers found that applying
glutathione (an antioxidant that is normally found in our cells)
directly on the skull surface after brain injury reduced the amount of
cell death by 67 percent.
When the researchers applied
glutathione three hours after injury, cell death was reduced by
51percent. “This idea that we have a time window within which to work,
potentially up to three hours, is exciting and may be clinically
important,” said Dr. McGavern.
Glutathione works by decreasing
levels of reactive oxygen species (ROS) molecules that damage cells. In
this study, high levels of ROS were observed at the trauma site right
after the physical brain injury occurred. The massive flood of ROS set
up a sequence of events that led to cell death in the brain, but
glutathione was able to prevent many of those effects.
In addition, using a powerful
microscopic technique, the researchers filmed what was happening just
beneath the skull surface within five minutes of injury. They captured
never-before-seen details of how the brain responds to traumatic injury
and how it mobilizes to defend itself.
Initially, they saw cell death in
the meninges and at the glial limitans (a very thin barrier at the
surface of the brain that is the last line of defense against dangerous
molecules). Cell death in the underlying brain tissue did not occur
until 9-12 hours after injury. “You have death in the lining first and
then this penetrates into the brain tissue later. The goal of therapies
for brain injury is to protect the brain tissue,” said Dr. McGavern.
Almost immediately after head
injury, the glial limitans can break down and develop holes, providing a
way for potentially harmful molecules to get into the brain. The
researchers observed microglia (immune cells that act as first
responders in the brain against dangerous substances) quickly moving up
to the brain surface, plugging up the holes.
The leading causes of TBI are:
• Falls (35.2%);
• Motor vehicle – traffic (17.3%);
• Struck by/against events (16.5%); and
• Assaults (10%).
• Falls continued to be the leading cause of TBI (35.2%) in
the United States. Falls cause half (50%) of the TBIs among
children aged 0 to 14 years and 61% of all TBIs among adults
aged 65 years and older.
Motor Vehicle-Traffic Crashes
• Among all age groups, motor vehicle crashes and
traffic-related incidents were the second leading cause of TBI
(17.3%) and resulted in the largest percentage of TBI-related
Findings from Dr. McGavern’s lab
indicate that microglia do this in two ways. According to Dr. McGavern,
“If the astrocytes, the cells that make up the glial limitans, are still
there, microglia will come up to ‘caulk’ the barrier and plug up gaps
between individual astrocytes.
If an astrocyte dies, that results
in a larger space in the glial limitans, so the microglia will change
shape, expand into a fat jellyfish-like structure and try to plug up
that hole. These reactions, which have never been seen before in living
brains, help secure the barrier and prevent toxic substances from
getting into the brain.”
Mild traumatic brain injuries are a
growing public health concern. According to a report from the Centers of
Disease Control and Prevention, in 2009 at least 2.4 million people
suffered a traumatic brain injury and 75 percent of those injuries were
mild. This study provides insight into the damage that occurs following
head trauma and identifies potential therapeutic targets, such as
antioxidants, for reducing the damaging effects.
NINDS is the nation’s leading funder of research on the brain and
nervous system. The NINDS mission is to reduce the burden of
neurological disease – a burden borne by every age group, by every
segment of society, by people all over the world.
About the Center for Neuroscience
and Regenerative Medicine (CNRM): The Center for Neuroscience and
Regenerative Medicine (CNRM) is a collaborative intramural federal
program involving the
U.S. Department of Defenseand
National Institutes of Health to bring together the expertise of
clinicians and scientists across disciplines to catalyze innovative
approaches to traumatic brain injury (TBI) research.
About the National Institutes of Health (NIH):
NIH, the nation's medical research agency, includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and Human
Services. NIH is the primary federal agency conducting and supporting
basic, clinical, and translational medical research, and is
investigating the causes, treatments, and cures for both common and rare
diseases. For more information about NIH and its programs, visit
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