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Different approach needed to protect brains of premature infants

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,\\\

Washington University School of Medicine