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By
Michael Purdy
April
11, 2007 -- A study of how the brain of a premature
infant responds to injury has found vulnerabilities
similar to those in the mature brain but also identified
at least one significant difference, according to neuroscientists
and neonatologists at Washington University School of
Medicine in St. Louis.
In
an animal model of brain injury, researchers showed
for the first time that parts of the developing brain
are vulnerable to damage from glutamate, a nervous system
messenger compound. Glutamate is already well-known
for its links to injury in the mature brain. But scientists
also found damage in the developing brain that could
not be linked to glutamate, suggesting that different
treatments are needed to prevent brain injury in premature
infants.
More
than two percent of babies are born before the completion
of their eighth month of gestation, and up to half of
these infants suffer brain injury. Unlike adults, premature
infants receive the most damage in the white matter,
the portions of the brain that connect different brain
regions. "These
injuries can lead to behavioral problems, developmental
delay, cognitive impairment or cerebral palsy,"
says senior author Mark P. Goldberg, M.D., professor
of neurology and of neurobiology. "In this study,
we've identified a unique vulnerability in the developing
brain's white matter that likely contributes to those
disabilities. We will be looking for new drug treatments
to prevent injury."
The
research, reported in the April 11 issue of The Journal
of Neuroscience, was conducted at the Hope Center for
Neurological Disorders, a partnership between the University
and Hope Happens, a St. Louis-based nonprofit organization
dedicated to raising funds for neurological research.
Goldberg is director of the center. Goldberg
and lead author William J. McCarran, M.D., a neonatology
fellow in the Department of Pediatrics, worked with
a "slice-based" model of injury's effects
on the developing brain. Goldberg says the model strikes
a compromise between the confounding factors present
in whole animal models and the limitations of studying
single brain cells in culture.
"In
whole animals, it's difficult to separate out what makes
the brain uniquely vulnerable, and in cell cultures
the neurons aren't really in their proper environment,"
he says. "For our model, we use mouse brain slices
that we can keep alive for 12 hours. That keeps all
the connections, structures and cell types intact and
in their proper relationship. Our ability to observe
these connections at the microscopic level provides
a new window for understanding perinatal brain injury."
To
probe how the brain's response to injury changes, researchers
took slices from the brains of mice of different ages.
At birth, the mouse brain's development lags somewhat
behind the human brain. A 3-day-old mouse brain, for
example, is roughly equivalent to the human brain during
the sixth to seventh month of gestation. Scientists
studied slices from 3-, 7-, 10- and 21-day-old mice.To
simulate injury, researchers deprived the slices of
oxygen and glucose for one hour. At all ages, the resulting
damage hit hardest on glial cells, support cells that
surround, nourish and protect brain cells; and axons,
the treelike branches that brain cells use to communicate
with each other. Studies of the brains of premature
babies have found a similar pattern of injury.
Researchers
for many years have linked brain damage to the effects
of glutamate. When Goldberg and McCarran used drugs
to block a glutamate receptor prior to cutting off oxygen
and glucose, it reduced injury with one noteworthy exception.
"In
the three-day-old mouse brain slices, the blockers couldn't
prevent damage to the axons," Goldberg says. "So
something other than glutamate is killing the axons
at that point in brain development."
In
the early brain, axons lack a protective sheath called
myelin. Glial cells supply this sheath, which is made
mostly of lipids and makes about 50 percent of the human
brain appear white, rather than gray. Goldberg and others
have been developing a theory that much of the harm
done by strokes and other brain injury begins in this
white matter. They suspect that damage to connections
between brain cells eventually leads to the cells' deaths.
Using
the slice model, researchers plan follow-up studies
of axons before they're coated in myelin and of potential
protective compounds.
"This
model turns out to be a powerful tool for seeking out
and testing new drugs, so we want to test a number of
new pharmaceuticals to see if any can protect axons
early in brain development," Goldberg says.
McCarran
WJ, Goldberg MP. White matter axon vulnerability to
AMPA/kainate receptor-mediated ischemic injury is developmentally
regulated. The Journal of Neuroscience, April 11, 2007.
Funding
from the National Institute of Child Health and Development
and the National Institutes of Health supported this
research.
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